Reactive Cellular Changes Associated With Inflammation


Reactive Cellular Changes Associated With Inflammation

What is reactive cellular changes associated with inflammation?

Negative for intraepithelial lesion or malignancy – This category means that no signs of cancer, pre-cancer, or other significant abnormalities were found. There may be findings that are unrelated to cervical cancer, such as signs of infection with yeast, herpes, or Trichomonas vaginalis (a type of sexually transmitted disease), for example.

What does cellular changes associated with inflammation mean on a Pap smear?

What did my Pap smear show? – A Pap smear allows your doctor to look at cells from your cervix to see if there are any problems. Your Pap smear has shown one or more of the following changes. Ask your doctor which of these changes you have. ASCUS (say “ask-us”) stands for atypical squamous cells of undetermined significance.

  • The squamous cells of your cervix were slightly abnormal on your Pap smear.
  • ASCUS may be caused by a vaginal infection or an infection with a virus called HPV (human papillomavirus, or wart virus).
  • Your doctor will talk with you about the options of looking at your cervix with a microscope (colposcopy) or repeating your Pap smear every six months for two years.

AGUS stands for atypical glandular cells of undetermined significance. These cells were slightly abnormal on your Pap smear. AGUS can occur with infections or with a change in the cells on the surface of your cervix or in the canal of your cervix. Your doctor will tell you how the abnormal results on your Pap smear need to be evaluated.

Your doctor may recommend repeat Pap smears or colposcopy. LSIL stands for low-grade squamous intraepithelial lesion. This is a common condition of the cells of the cervix and often occurs when the HPV wart virus is present. These changes in the cervix can be present even if you and your sexual partner are monogamous and have never had visible warts.

Changes caused by LSIL often get better with time. Your doctor will talk with you about whether you need to have Pap smears every six months for two years or whether you should have colposcopy. If inflammation (redness) is present in the cells on the Pap smear, it means that some white blood cells were seen on your Pap smear.

  1. Inflammation of the cervix is common and usually does not mean there is a problem.
  2. If the Pap smear showed that the inflammation is severe, your doctor may want to find the cause, such as an infection.
  3. You may also need to have another Pap smear in six months to see if the inflammation has gone.
  4. Hyperkeratosis is a finding of dried skin cells on your Pap smear.

This change in the cells of the cervix often occurs from cervical cap or diaphragm use or from infection. Hyperkeratosis usually does not need any more evaluation than a repeat Pap smear in six months. If it is still present on the repeat Pap smear, your doctor may want to repeat the test in another six months or perform colposcopy.

What are the reactive changes associated with inflammation in the Pap smear?


  • Cytoplasmic reactions to inflammation include degenerative and/or reactive changes. Pale staining of the cytoplasm or narrow zones of clearing around the nucleus – the inflammatory perinuclear halo which is particularly seen in Trichomonas infestation, also known as the “trich halos” (they can trick the unwary by mimicking the koilocytes). As a rule, the width of an inflammatory halo (i.e., the space between the nucleus and cytoplasm) is less than the diameter of an intermediate cell nucleus and the outline or the boundary of this halo is often vague or poorly defined, These are also known as the pseudokoilocytes, The halos of koilocytes are much larger, more sharply defined and their nuclei are big and dark. Polymorphs are seen many times permeating the cytoplasmic vacuolation, (a) “Trich halos” plenty TV are seen in the smear (red arrow). (b) Non-specific inflammatory perinuclear clearing and binucleation can mimic koilocytes (red arrow). However, there is no nuclear atypia (×40). LBC smear – engulfed leukocyte in a cytoplasmic vacuole (upper arrow). Trichomonas vaginalis is seen in the lower half (lower arrow) of the field (×40).
  • Vacuolar cytoplasmic degeneration is a common inflammatory change. Vacuolar degeneration of cytoplasm, pale degenerating swollen nuclei with indistinct chromatin and loss of the sharp details of the nuclear envelope are additional features, The cells appear frayed, ragged, or moth-eaten eventually leading to cytolysis. Vacuolar degeneration is particularly common in metaplastic cells. Moreover, when this is associated with nuclear atypia, it can be mistaken for a koilocyte. However, these cells appear smaller than a koilocyte and the classical nuclear features of the latter are also missing, Squamous cells with a large single vacuole pushing the nucleus to the periphery, giving a soap bubble appearance, are also seen in the Pap smear collected from the IUCD wearers. The combination of vacuolated cytoplasm and atypical nuclei may also suggest adenocarcinoma (a) LBC smear showing vacuolar degeneration of cytoplasm with pale degenerating swollen nuclei with indistinct chromatin and loss of the sharp details of the nuclear envelope. (b) Same features seen in CP smear (×40). (a) CP smear – Pseudokoilocytes – metaplastic cells showing cytoplasmic vacuolation, however, nuclear atypia is lacking – CP smear. (b) LBC smear – Pseudokoilocyte – metaplastic cells showing cytoplasmic vacuolation, however, nuclear atypia is lacking. Smear is showing pseudokoilocyte along with Candida infection (×40).
  • Reactive changes include parakeratosis, dyskeratosis, and hyperkeratosis. Parakeratotic cells are miniature keratinized squamous cells with pyknotic nuclei and dense eosinophilic cytoplasm resulting from surface keratinization (generally seen in psoriasis). This abnormality of the cervix epithelium was named pseudoparakeratosis, Dyskeratosis involves premature or excessive keratinization of individual squamous cells that are spread sparsely throughout the smear. The cytoplasm of these cells is dense orangeophilic. The N/C ratio is normal and nuclear outlines are smooth. Hyperkeratosis is associated with nucleated squamous cells (squames), of characteristic pale yellow color in Papanicolaou stain, and are shed from the surface of the keratinized squamous epithelium, The presence of dyskeratotic, atypical parakeratotic cells and anucleated squamous cells should be mentioned in the report because of the remote possibility that these cells may have originated from the surface of a warty lesion (HPV associated) or squamous cancer masquerading as leukoplakia, Such patients deserve a closer clinical look and HPV DNA test for high-risk viruses followed by colposcopy if necessary. In squamous carcinomas with the features of leukoplakia, anucleated squamous cells are usually accompanied by cells with abnormal, hyperchromatic nuclei that allow an accurate diagnosis. CP smear – parakeratosis – these are small superficial squamous cells with sharply outlined cytoplasmic margins and small pyknotic nuclei. Inset showing histopathology of the same (×40). CP smear – keratinized plaque of orange keratotic material from a hyperkeratotic squamous epithelium. Cell borders are indistinct. Inset showing histopathology of the same (×40). CP smear – dyskeratosis and atypical parakeratosis: Small round to oval polygonal to spindle cells with dense eosinophilic cytoplasm and pyknotic hyperchromatic and mildly pleomorphic nuclei. These may camouflage a more serious lesion. Compare with cells of Figure 12 that are appearing as a benign reaction to inflammation (×40).
  • Staining alterations: Intermediate, parabasal, and metaplastic cells sometimes become eosinophilic or orangeophilic, staining dense pink to orange instead of green. This is commonly seen in senile vaginitis or atrophic smears. Pseudokeratinized cytoplasm with atypical nuclei may mimic low-grade keratinizing dysplasia. Polychromasia or two-tone staining of the cytoplasm – pink and blue or green – may occur or cytoplasm may stain less intensely as a result of inflammation, (a) Polychromasia or two-tone cytoplasm (red arrow) are seen in squamous cells of an inflammatory smear. Benign binucleation is seen at the arrows. (b) Binucleation and bland nucleomegaly in an inflammatory smear (×40).

Nuclear changes: Nuclear features are a key to distinguishing reactive and degenerative changes from dysplasia. The nucleus in inflammatory smears is big but not dark as is seen in dysplasia where it is both – big and dark. More frequently observed is the bland enlarged nucleus with pale staining chromatin due to fluid absorption. Chromatin may be indistinct and smudgy rather than crisp and distinct, These changes vary from cell to cell resulting in the prominence of anisonucleosis, By and large, the nuclear size remains <2 times the size of an intermediate cell nucleus. Wrinkling of the nuclear membrane and central clearing with selective condensation of the chromatin at the periphery are other degenerative changes. This may be associated with common degenerative changes associated with inflammation such as karyopyknosis, karyorrhexis, and karyolysis. Hyperchromasia, binucleation, and the presence of nucleoli favor a reactive process, However, the contours of the nucleus are smooth and round and this change is uniformly seen in most cells, As a general rule, the differences between inflammatory change and dysplasia are a matter of degree. (a) CP smear – minimal hyperchromasia (red arrow), binucleation, anisonucleosis, and nuclear enlargement and smooth nuclear contours favor reactive cellular changes associated with inflammation (×40). (b) LBC smear – minimal hyperchromasia, binucleation, anisonucleosis, and nuclear enlargement and smooth nuclear contours favor reactive cellular changes associated with inflammation (×40).

Features favoring reactive/inflammatory changes include slight nuclear enlargement (<×2 an intermediate cell nucleus), smooth nuclear membranes, fine pale chromatin, conspicuous nucleoli may be present, inflammatory perinuclear halos (differential koilocyte halos), cytoplasmic fraying, vacuolation, polychromasia, and pseudokeratinization. The background is not clean and may be "dirty" with granular and fibrinous debris that tends to cling to epithelial cells in LBP.

What are the reactive cellular changes present?

Abstract – Reactive cell change in cervicovaginal smears is a controversial issue. The most common criteria for reactive cell change include an increase in nuclear size, presence of nucleoli, binucleation, cytoplasmic vacuolization, and polychromasia.

  • The purpose of this study is to define, as specifically as possible, the criteria of reactive cell change.
  • Sixty-one cervicovaginal smears in a routine examination obtained during 1988 to 1994 were reviewed for this study.
  • All cases had been diagnosed as reactive.
  • Fifty-three of these were re-diagnosed as reactive and 8 cases were rediagnosed as negative.

Inflammatory cells were present in 79% and organisms involvement such as Herpes, Trichomonas, Chlamydia, Gardnerella, and Candida were present in 23% percent. The smears were also evaluated for cellular arrangement, origin of the reactive cells, and presence of nucleoli.

  1. The majority of reactive cells were found in aggregates and were of metaplastic origin.
  2. Nucleoli were present in 85% of the cases.
  3. In all cases the most important criteria of reactive cell change were found to be aggregates of metaplastic cells with central nuclei containing nucleoli and a fine chromatin pattern, followed by the presence of organisms.

Additionally, the majority of cases with a cytology diagnosis of reactive cell change had a squamous intraepithelial lesion on biopsy. In conclusion, this study suggests that follow-up Pap smears over a two year period may revert to normal in some of the cases.

What does reactive changes mean on biopsy?

What are reactive changes? – In pathology, the term ‘reactive changes’ is used to describe cells or tissues that look abnormal as a result of changes in their environment. These changes can include infection, physical injury, medication, and inflammation, Reactive changes are benign (non-cancerous). This picture shows reactive changes caused by a type of injury called an ulcer.

Is inflammation on Pap smear normal?

What Does Inflammation On a Pap Smear Mean? What is the recommendation for monitoring or treating Pap smear results that show inflammation without any other abnormalities? Is this age-dependent? — Mary Ryan, MSN, ARNP, FNP-C, Shawnee Mission, KS Inflammation on a Pap smear can be found in a patient of any age and may be attributable to a benign infection — such as Candida vaginitis — that need be treated only if the patient is symptomatic.

Sexually transmitted infections can also cause an inflammatory reaction on the cervix and should be treated accordingly. If a Pap result comes back as “inflammation,” but the smear is otherwise satisfactory (assuming the previous test was satisfactory and normal), the Pap should be repeated in one year.

The one exception would be if the patient is HIV-positive, in which case she needs a follow-up Pap in four to six months. There have been many recent changes in the recommendations as to how frequently Pap smears should be done. Although the main professional organizations (i.e., the American Cancer Society, the U.S.

  1. Preventive Services Task Force, and the American Congress of Obstetricians and Gynecologists) vary somewhat in their recommendations, the overarching message from all three is that health-care professionals are doing Pap smears too frequently.
  2. The rationale behind this assertion is that cervical cancer is slow-growing and therefore it can be adequately screened at less frequent intervals than every year.

Too-frequent Pap smears lead to many unnecessary procedures and treatments, some of which put women at an increased risk of such pregnancy complications as preterm labor. — Mary Newberry, CNM, MSN (166-1) This article originally appeared on : What Does Inflammation On a Pap Smear Mean?

What causes cellular changes associated with inflammation?

The most important feature of inflammation is the accumulation of white blood cells at the site of injury. Most of these cells are phagocytes, certain “cell-eating” leukocytes that ingest bacteria and other foreign particles and also clean up cellular debris caused by the injury.

  1. The main phagocytes involved in acute inflammation are the neutrophils, a type of white blood cell that contains granules of cell-destroying enzymes and proteins.
  2. When tissue damage is slight, an adequate supply of these cells can be obtained from those already circulating in the blood.
  3. But, when damage is extensive, stores of neutrophils—some in immature form—are released from the bone marrow, where they are generated.

To perform their tasks, not only must neutrophils exit through the blood vessel wall but they must actively move from the blood vessel toward the area of tissue damage. This movement is made possible by chemical substances that diffuse from the area of tissue damage and create a concentration gradient followed by the neutrophils.

The substances that create the gradient are called chemotactic factors, and the one-way migration of cells along the gradient is called chemotaxis, Large numbers of neutrophils reach the site of injury first, sometimes within an hour after injury or infection. After the neutrophils, often 24 to 28 hours after inflammation begins, there comes another group of white blood cells, the monocytes, which eventually mature into cell-eating macrophages,

Cervical cytology HCGs – Reactive change

Macrophages usually become more prevalent at the site of injury only after days or weeks and are a cellular hallmark of chronic inflammation.

Are reactive cellular changes associated with inflammation or repair are present?


  • “REACTIVE AND OR REPARATIVE CELLULAR CHANGES NOTED” Reactive changes that are benign in nature, associated with inflammation (includes typical repair), atrophy with inflammation (“atrophic vaginitis”), radiation, an IUD, and other nonspecific causes. This designation includes reparative changes or “typical repair”, which may involve squamous epithelium, squamous metaplasia or columnar epithelium.

What causes cellular inflammation?

Abstract – Inflammation is a biological response of the immune system that can be triggered by a variety of factors, including pathogens, damaged cells and toxic compounds. These factors may induce acute and/or chronic inflammatory responses in the heart, pancreas, liver, kidney, lung, brain, intestinal tract and reproductive system, potentially leading to tissue damage or disease.

Both infectious and non-infectious agents and cell damage activate inflammatory cells and trigger inflammatory signaling pathways, most commonly the NF-κB, MAPK, and JAK-STAT pathways. Here, we review inflammatory responses within organs, focusing on the etiology of inflammation, inflammatory response mechanisms, resolution of inflammation, and organ-specific inflammatory responses.

Keywords: inflammation, inflammatory signaling pathways, chemokines, cytokines, organ diseases

What is cervix inflammation and reactive changes?

Cervicitis – With cervicitis, an inflammation of your cervix, your cervix appears red and irritated and may produce a pus-like discharge. Most often, cervicitis causes no signs and symptoms, and you may only learn you have the condition after a pelvic exam performed by your doctor for another reason. If you do have signs and symptoms, they may include:

Large amounts of unusual vaginal discharge Frequent, painful urination Pain during sex Bleeding between menstrual periods Vaginal bleeding after sex, not associated with a menstrual period

How do you treat an inflammatory smear?

Treatment of Inflammatory Cytologic Abnormalities Detected By Pap Abstract & Commentary Synopsis: There appears to be no clinical benefit to treatment of inflammatory cytologic abnormalities. Source: Webb J, et al. Journal of Lower Genital Tract Disease,2001;5(2):82-84.

For many years, it has been the practice of many clinicians to prescribe intervaginal or oral antibiotic therapy to patients who have a Pap smear showing inflammatory cytologic abnormalities. The rationale for such therapy has been repeatedly questioned yet the practice persists. Webb and associates in this pilot study asked all women who had a Pap smear report which showed inflammatory cytologic abnormalities at their institution to participate in this study.

Patients who agreed were assigned to 1 of 2 oral metronidazole regimens, vaginal metronidazole, or no therapy. This study included 159 women. The method of patient assignment did not result in equal sized treatment groups. However, when the data from the 4 groups were compared, Webb et al could not demonstrate a statistically significant difference among the groups.

Webb et al conclude that empiric antibiotic treatment of women with inflammatory changes on Pap smears is not clinically indicated. Comment by Kenneth L. Noller, MD I have always wondered where the practice of treating inflammatory cells on Pap smears with antibiotics came from. The test was not designed to detect infection, and the presence of such cells does not mean an infection is present.

The fact that there are some white cells present on the slide does not mean that anything needs to be, or should be treated. Even though cervical cytology can detect the presence of fungal organisms, changes consistent with BV, and trichomonads it is not clear that any of these should be treated unless the patient has symptoms.

Indeed, in the revision of the Bethesda terminology that is currently being considered the whole category of “benign cellular changes” is probably going to be eliminated. While this was not a great study (lack of randomization of treatment arms, nonblinding, inadequate sample size, etc) it did fail to detect any significant difference in Pap smear reports subsequent to antibiotic therapy vs.

placebo. There have been prospective, randomized, clinical trials performed and they also have failed to detect any basis for treatment of inflammatory smears with antibiotics. Unfortunately, the practice persists. You have reached your article limit for the month.

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Financial Disclosure: None of the authors or planners for this educational activity have relevant financial relationships to disclose with ineligible companies whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients : Treatment of Inflammatory Cytologic Abnormalities Detected By Pap

What causes inflammation of the cervix?

Cervicitis is the inflammation of the cervix. It is usually caused by an infection but may also be caused by chemical exposure or the presence of a foreign body.

What is cellular inflammation response?

The immune response is how your body recognizes and defends itself against bacteria, viruses, and substances that appear foreign and harmful. The immune system protects the body from possibly harmful substances by recognizing and responding to antigens,

  1. Antigens are substances (usually proteins) on the surface of cells, viruses, fungi, or bacteria.
  2. Nonliving substances such as toxins, chemicals, drugs, and foreign particles (such as a splinter) can also be antigens.
  3. The immune system recognizes and destroys, or tries to destroy, substances that contain antigens.

Your body’s cells have proteins that are antigens. These include a group of antigens called HLA antigens, Your immune system learns to see these antigens as normal and usually does not react against them. INNATE IMMUNITY Innate, or nonspecific, immunity is the defense system with which you were born.

Cough reflexEnzymes in tears and skin oilsMucus, which traps bacteria and small particlesSkinStomach acid

Innate immunity also comes in a protein chemical form, called innate humoral immunity. Examples include the body’s complement system and substances called interferon and interleukin-1 (which causes fever). If an antigen gets past these barriers, it is attacked and destroyed by other parts of the immune system.

  • ACQUIRED IMMUNITY Acquired immunity is immunity that develops with exposure to various antigens.
  • Your immune system builds a defense against that specific antigen.
  • PASSIVE IMMUNITY Passive immunity is due to antibodies that are produced in a body other than your own.
  • Infants have passive immunity because they are born with antibodies that are transferred through the placenta from their mother.

These antibodies disappear between ages 6 and 12 months. Passive immunization may also be due to injection of antiserum, which contains antibodies that are formed by another person or animal. It provides immediate protection against an antigen, but does not provide long-lasting protection.

Immune serum globulin (given for hepatitis exposure) and tetanus antitoxin are examples of passive immunization. BLOOD COMPONENTS The immune system includes certain types of white blood cells. It also includes chemicals and proteins in the blood, such as antibodies, complement proteins, and interferon.

Some of these directly attack foreign substances in the body, and others work together to help the immune system cells. Lymphocytes are a type of white blood cell. There are B and T type lymphocytes.

B lymphocytes become cells that produce antibodies. Antibodies attach to a specific antigen and make it easier for the immune cells to destroy the antigen.T lymphocytes attack antigens directly and help control the immune response. They also release chemicals, known as cytokines, which control the entire immune response.

As lymphocytes develop, they normally learn to tell the difference between your own body tissues and substances that are not normally found in your body. Once B cells and T cells are formed, a few of those cells will multiply and provide “memory” for your immune system.

  1. This allows your immune system to respond faster and more efficiently the next time you are exposed to the same antigen.
  2. In many cases, it will prevent you from getting sick.
  3. For example, a person who has had chickenpox or has been immunized against chickenpox is immune from getting chickenpox again.
  4. INFLAMMATION The inflammatory response (inflammation) occurs when tissues are injured by bacteria, trauma, toxins, heat, or any other cause.

The damaged cells release chemicals including histamine, bradykinin, and prostaglandins. These chemicals cause blood vessels to leak fluid into the tissues, causing swelling, This helps isolate the foreign substance from further contact with body tissues.

The chemicals also attract white blood cells called phagocytes that “eat” germs and dead or damaged cells. This process is called phagocytosis. Phagocytes eventually die. Pus is formed from a collection of dead tissue, dead bacteria, and live and dead phagocytes. IMMUNE SYSTEM DISORDERS AND ALLERGIES Immune system disorders occur when the immune response is directed against body tissue, is excessive, or is lacking.

Allergies involve an immune response to a substance that most people’s bodies perceive as harmless. IMMUNIZATION Vaccination ( immunization ) is a way to trigger the immune response. Small doses of an antigen, such as dead or weakened live viruses, are given to activate immune system “memory” (activated B cells and sensitized T cells).

Memory allows your body to react quickly and efficiently to future exposures. COMPLICATIONS DUE TO AN ALTERED IMMUNE RESPONSE An efficient immune response protects against many diseases and disorders. An inefficient immune response allows diseases to develop. Too much, too little, or the wrong immune response causes immune system disorders.

An overactive immune response can lead to the development of autoimmune diseases, in which antibodies form against the body’s own tissues. Complications from altered immune responses include:

Allergy or hypersensitivity Anaphylaxis, a life-threatening allergic reactionAutoimmune disorders Graft versus host disease, a complication of a bone marrow transplantImmunodeficiency disorders Serum sickness Transplant rejection

Updated by: Stuart I. Henochowicz, MD, FACP, Clinical Professor of Medicine, Division of Allergy, Immunology, and Rheumatology, Georgetown University Medical School, Washington, DC. Also reviewed by David Zieve, MD, MHA, Medical Director, Brenda Conaway, Editorial Director, and the A.D.A.M. Editorial team.

What are reactive cells?

1 Introduction – Forms of cardiovascular disease (CVD) such as stroke and myocardial infarction are some of the most common causes of death worldwide. In fact, the World Health Organization reports CVD to be responsible for about one-third of deaths globally in 2015,

  • In response to this, many prophylactic and therapeutic strategies based around diet management have been developed for treating patients with CVD.
  • One of the most important factors involved in cardiovascular diseases is increased blood platelet activation, especially hyperaggregation of blood platelets.

Platelets (at concentrations of 150–400 × 10 9 per mL) serve as one of the key elements of blood. They are highly- reactive cells, which undergo activation following exposure to agonists (called also activators) such as thrombin, arachidonic acid, adenosine diphosphate (ADP) or collagen.

  • For example, ADP was the first low-molecular-weight platelet aggregating agent to be identified.
  • The platelet receptor for ADP has been classified as a P 2T receptor of the P 2 purinoreceptor family.
  • The response of blood platelet (called blood platelet activation) to agonists includes adhesion to foreign surface (collagen, fibrinogen or other adhesive proteins), shape change, aggregation and secretion of different biological active compounds from storage granules (alpha-granules, dense granules and lysosomes), shedding of microvescicles, formation of blood platelet procoagulant properties and retraction of fibrin clots.

Platelet agonists initiate platelet activation by binding to receptors on blood platelet surface. This activation is associated not only with morphological changes, but also with biochemical processes, such as arachidonic acid metabolism associated with the eicosanoid synthesis, phosphoinositide hydrolysis and reactive oxygen species (ROS) production.

The major metabolite of arachidonic acid in blood platelets is thromboxane A 2 (TXA 2 ), which functions as an ultimate activator of platelets. In contract, prostaglandins—PGI 2 and PGD 2 (which are also metabolites of arachidonic acid) inhibit platelet activation. In addition, blood platelet activation results in the elevation of intracellular calcium concentration,

In platelets, there are several sources of ROS: metabolism of phosphoinositides, metabolism of arachidonic acid, and glutathione cycle. Moreover, ROS are produced by activation of xantine oxidase and NAD(P)H oxidase. Platelets may also synthesize various reactive nitrogen species (RNS), including nitric oxide (˙NO).

ROS and RNS may behave as second messengers and may regulate blood platelet functions. On the other hand, an increase of ROS/RNS may induce the oxidative stress associated with development of cardiovascular diseases, An important step of platelet activation is platelet aggregation, in which platelets interact with one another to form a hemostatic plug or thrombus.

It has known that the platelet membrane glycoprotein (GP) IIb and IIIa are essential for platelet aggregation. This process may be inhibited by various compounds using a range of mechanisms, and these can be used in the prophylaxis and treatment of CVD associated with blood platelet hyperactivation.

This chapter presents the current state of knowledge concerning the anti-platelet potential of plant oils (especially oil ingredients—fatty acids), and compares it with that of better-known and more popular fish oils; it also examines whether plant oils are better sources of bioactive ingredients with anti-platelet activity, which can play a role in the prophylaxis and treatment of cardiovascular diseases.

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What is inflammation?

When a wound swells up, turns red and hurts, it may be a sign of inflammation. Very generally speaking, inflammation is the body’s immune system’s response to an irritant. The irritant might be a germ, but it could also be a foreign object, such as a splinter in your finger.

What does it mean when a biopsy shows inflammation?

GLOSSARY OF IMPORTANT DIAGNOSTIC TERMS – Finally, it may be useful to present a brief glossary of important terms used in pathologic diagnoses. Terms in the definition that are in ALL CAPS have their own entry. ABSCESS A closed pocket containing pus. Some abscesses are easily diagnosed clinically, as they are painful and may “point out” such that pus becomes visible, but deep and chronic abscesses may just look like a TUMOR clinically and require biopsy to distinguish them from neoplasm.

ATYPICAL The simple, straightforward definition would be “unusual,” but “atypical” means much more than that. In a diagnosis, the use of the term atypical is a vague warning to the physician that the pathologist is worried about something, but not worried enough to say that the patient has cancer. For instance, lymphomas (cancers of the lymph nodes) are notoriously difficult to diagnose.

Some lymph node biopsies are very disturbing but do not quite fulfill the criteria for cancer. Such a case may be diagnosed as “atypical lymphoid HYPERPLASIA.” Other important atypical hyperplasias are those of the breast (atypical ductal hyperplasia and atypical lobular hyperplasia) and the lining of the uterus (atypical endometrial hyperplasia).

  • Both of these conditions are thought to be precursor warning signs that the patient is at high risk of developing cancer of the respective organ (breast and uterus).
  • CARCINOMA A malignant NEOPLASM whose cells appear to be derived from EPITHELIUM.
  • This word can be used by itself or as a suffix.
  • Cancers composed of columnar epithelial cells are often called adenocarcinomas.

Those of squamous cells are called squamous cell carcinomas. The type of cancer typically recapitulates the type of epithelium that normally lines the affected organ. For instance, almost all cancers of the colon are adenocarcinomas, and columnar epithelium is the normal lining of the colon.

There are exceptions, however. DYSPLASIA An ATYPICAL proliferation of cells. This may be loosely thought of as an intermediate category between HYPERPLASIA and NEOPLASIA. It finds its best use as a term to describe the phenomenon in which EPITHELIUM proliferates and develops the microscopic appearance of neoplastic tissue, but otherwise tends to “behave itself” and continues to line body surfaces without actually invading them, as a true malignant neoplasm would do.

It may be convenient (but not totally accurate) to consider dysplasia as a “pre-cancer” or an incipient cancer. Probably the most commonly occurring type of dysplasia is that of the cervix of the uterus, where a progression from dysplasia to neoplasia can be clearly demonstrated.

  1. Other dysplasias, such as those of the breast and prostate, are more difficult to clearly relate to neoplasia at this time.
  2. EPITHELIUM A specialized type of tissue that normally lines the surfaces and cavities of the body.
  3. There are three main types: 1) columnar epithelium, which lines the stomach, intestines, trachea and bronchi, salivary and other glands, pancreas, gallbladder, nasal cavity and sinuses, uterus (including inner cervix), Fallopian tubes, kidneys, testes, vasa deferentia, and other ductal structures, 2) stratified squamous epithelium, which lines the skin, oral cavity, throat, esophagus, anus, outer urethra, vagina, and outer cervix, and 3) transitional epithelium (urothelium), which lines the urine-collecting part of the kidneys, the ureters, bladder, and inside part of the urethra.

GRANULOMA A special type of INFLAMMATION characterized by accumulations of macrophages, some of which coalesce into “giant cells.” Granulomatous inflammation is especially characteristic of tuberculosis, some deep fungal infections (like histoplasmosis and coccidioidomycosis), sarcoidosis (a disease of unknown cause), and reaction to foreign bodies.

  1. HYPERPLASIA A proliferation of cells which is not NEOPLASTIC.
  2. In some cases, this may be a result of the body’s normal reaction to an imbalance or other stimulus, while in other cases the physiologic cause of the proliferation is not apparent.
  3. An example of the former process is the enlargement of lymph nodes in the neck as a result of reaction to a bacterial throat infection.

The lymphocytes which make up the node divide and proliferate, taking up more volume in the node and causing it to expand. An example of hyperplasia in which the stimulus is not known is benign prostatic hyperplasia (BPH), in which the prostate gland enlarges in older men for no known reason.

While hyperplasias do not invade other organs or METASTASIZE to other parts of the body, they can still cause problems because of their local physical expansion. For instance, in BPH, the enlarged prostate pinches off the urethra and interferes with the flow of urine. If untreated, permanent kidney damage can result.

INFLAMMATION A reaction, usually mediated by the immune system, to noxious stimuli, manifested clinically by swelling, pain, tenderness, redness, heat, and/or loss of function of the affected part. To a pathologist, however, inflammation means the infiltration of certain immune system cells into the tissue or organ being examined.

These inflammatory cells include 1) neutrophils, which are the white blood cells that make up pus and are seen in acute or early inflammations, 2) lymphocytes, which are typically seen in more chronic or longstanding inflammations, and 3) macrophages (histiocytes), which are also seen in chronic inflammation.

Some types of inflammation are readily diagnosable by the primary care physician, such as an infected skin wound that is tender, hot, and draining pus. Other types of inflammation are not so readily apparent clinically and require biopsy to distinguish them from neoplasms.

  1. The suffix “-itis” is appended to a root word to indicate “inflammation of _.” For example, cervicitis, pharyngitis, gastritis, and thyroiditis are inflammations of the cervix, pharynx (throat), stomach, and thyroid gland, respectively.
  2. LESION This is a vague term meaning “the thing that is wrong with the patient.” A lesion may be a TUMOR, an area of INFLAMMATION, or an invisible biochemical abnormality (like the abnormality of the sensitivity of the body’s cells to insulin in adult-onset diabetes).

METAPLASIA The phenomenon by which one type of tissue is replaced by another type. This often results from chronic irritation of an EPITHELIAL lining. A good example is the cervix, in which chronic irritation and INFLAMMATION causes the relatively delicate normal columnar epithelium to be replaced by tougher squamous epithelium (similar to that which normally lines the vagina, which is naturally “built tougher” for obvious reasons).

This phenomenon is called “squamous metaplasia.” In it’s pure state, metaplasia is not harmful, but some metaplasias are markers for increased risk of more serious diseases. For instance, a type of intestinal metaplasia of the stomach (in which columnar epithelium of the intestinal type replaces that of the gastric type) is considered a risk factor for the subsequent development of cancer of the stomach.

METASTATIC Of or pertaining to METASTASIS, or the process by which malignant NEOPLASMS can shed individual cells, which can travel through the lymph vessels or blood vessels, lodge in some distant organ, and grow into tumors in their own right. There are two major routes of metastasis, 1) hematogenous, in which the cells travel through the blood vessels, and 2) lymphogenous, in which the lymphatic vessels conduct the cancer cells.

  1. In the case of lymphogenous metastasis, the metastatic tumors can grow from cancers cells entrapped in the lymph nodes that collect the lymph draining from the organ where the original cancer has developed, causing the nodes to enlarge.
  2. In the case of breast cancer, the axillary (underarm) nodes are the first to become involved.

In the case of cancer of the larynx (voice box), the nodes on either side of the neck (cervical nodes) are first. Hematogenous metastases tend to deposit in the lungs, liver, and brain. Many cancers metastasize both lymphogenously and hematogenously. Most cancer operations attempt to remove not only the cancerous organ, but also the lymph nodes that drain that organ.

Some types of cancer, especially the most common ones (lung, breast, colon, and prostate cancers) tend to metastasize to lymph nodes first. Pathologic examination of these nodes is important in “staging” the cancer, which gives the patient and the doctor some idea as to the odds of curing the cancer and how to best treat it.

A typical diagnosis of a specimen of a “radical” removal of a cancer may read like, Breast, left, mastectomy: infiltrating ductal cancinoma; three of fifteen axillary nodes contain metastatic carcinoma. NECROSIS Death of tissue. Necrosis may be seen in inflammatory conditions, as well as in NEOPLASMS.

  1. NEOPLASM, or NEOPLASIA A “new growth” of the body’s own cells, a proliferation of cells no longer under normal physiologic control.
  2. These may be “benign” or “malignant.” Benign neoplasms are typically tumors (lumps or masses) that, if removed, never bother the patient again.
  3. Even if they are not removed, they are not capable of destroying adjacent organs or “seeding” out to other parts of the body.

Malignant neoplasms, or “cancers,” are those whose natural history (i.e., behavior if untreated) is to cause the death of the patient. Malignancy is expressed by 1) local invasion, in which the neoplasm extends into vital organs and interferes with their function, 2) METASTASIS, in which cells from the tumor seed out to other parts of the body and then grow into tumors themselves, and/or 3) paraneoplastic syndromes, in which the neoplasm secretes metabolic poisons or inappropriately large amounts of hormones that cause problems with functions of various body systems.

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OMA This suffix means “tumor” or “lump.” It typically, but not invariably, refers to a NEOPLASM (“GRANULOMA” is an exception). In referring to neoplasms, benign ones are typically referred to by a word, the prefix of which refers to the organ or tissue of origin, followed by the suffix “-oma.” For example, leiomyoma, osteoma, chondroma, adenoma, and hemangioma, refer to benign neoplasms of smooth muscle, bone, cartilage, glandular tissue, and blood vessel tissue, respectively.

The analogous terms for malignant versions of these neoplasms are, leiomyo SARCOMA, osteosarcoma, chondrosarcoma, adeno CARCINOMA, and angiosarcoma. There are exceptions to these vocabulary rules. For instance, hepatomas and melanomas are all malignant.

  • Other tumors, such as those of the adrenal glands, cannot be classified into benign or malignant categories based on pathologic appearance.
  • Only their behavior in time shows their true colors.
  • An example is pheochromocytoma (a tumor of the adrenal medulla), ten per cent of which are malignant, but we don’t know just by looking at the tumor if a given case will fall into that ten per cent.

POLYP A structure consisting of a rounded head attached to a surface by a stalk (also called a “pedicle” or “peduncle”). A mushroom growing from the soil is an excellent example of what a polyp looks like. Polyps my be HYPERPLASTIC, METAPLASTIC, NEOPLASTIC, INFLAMMATORY, or none of the above.

  1. The typical polyps removed from the colon of adults during colonoscopy are benign neoplasms called tubular adenomas or adenomatous polyps.
  2. The typical nasal polyps that develop in people with allergies are inflammatory.
  3. The common benign polyps removed from the cervix are of uncertain origin.
  4. SARCOMA A malignant NEOPLASM whose cells appear to be derived from those other than EPITHELIUM.

The connective tissues of the body (fibrous tissue, muscle, bone, cartilage, fat, and lining of joints) tend to give rise to sarcomas. In adults, CARCINOMAS are much more common than sarcomas. This makes sense, because as we age, our body linings are assaulted by one noxious substance after the other.

So it is no surprise that those epithelial cells on the forefront of our battle with the environment are the first to lose control of their growth and development. In children, sarcomas make up a greater proportion of cancers. While the connective tissues of adults are rather stable and protected from environmental assault, those of children are still growing and developing, the cells dividing, raising the likelihood that something will go haywire and cause a cell to lose control over its growth.

SUPPURATION, SUPPURATIVE INFLAMMATION A type of acute INFLAMMATION characterized by infiltration of neutrophils at the microscopic level and formation of pus at the gross level. ABSCESS is special type of suppurative inflammation. TUMOR A mass or lump that can be felt with the hand or seen with the naked eye.

Do biopsies show inflammation?

If a condition has already been diagnosed, a biopsy can also be used to assess its severity (such as the degree of inflammation) and grade (such as the aggressiveness of a cancer). This information can be very useful for: deciding on the most appropriate treatment.

What are benign cellular changes in a Pap smear?

What are Benign Cellular Changes in Pap Smear? – Benign cellular changes in pap smear refer to the presence of abnormal cells in the cervix that are not cancerous. These changes are also known as atypical squamous cells of undetermined significance (ASC-US) or atypical glandular cells (AGC).

What should I do if I have mild inflammation in my Pap smear?

A Pap smear, also called a Pap test, is an exam a doctor uses to test for cervical cancer in women. It can also reveal changes in your cervical cells that may turn into cancer later. A Pap smear is done to look for changes in cervical cells before they turn into cancer,

If you have cancer, finding it early on gives you the best chance of fighting it. If you don’t, finding cell changes early can help prevent you from getting cancer. If you are between the ages of 21 and 65, you should have a Pap smear on a regular basis. How often you do depends on your overall health and whether or not you’ve had an abnormal Pap smear in the past.

You should have the test every 3 years from ages 21 to 65. You may choose to combine your Pap testing with human papillomavirus ( HPV ) testing starting at age 30. If you do so, then you can be tested every 5 years instead. HPV is the most common sexually transmitted infection (STI), and it’s linked to cervical cancer,

Cervical cancer or a Pap test that revealed precancerous cells HIV infectionA weakened immune system due to an organ transplant, chemotherapy, or chronic corticosteroid useHaving been exposed to diethylstilbestrol (DES) before birth

Talk to your doctor if you have questions or concerns. They’ll let you know for sure. If you are a transgender man or nonbinary person, it is still important to get regular Pap smears. Shop around to find a doctor who makes you feel comfortable. You shouldn’t have a Pap smear during your period.

Don’t have sex or use lubricants.Don’t use sprays or powders near your vagina,Don’t insert anything into your vagina, including tampons, medications, creams, and suppositories,Don’t rinse your vagina with water, vinegar, or other fluid (such as a douche).

It takes about 10-20 minutes for the whole exam, but only a few minutes for the actual Pap smear. The test is done in your doctor’s office or clinic. You’ll lie on a table with your feet placed firmly in stirrups. You’ll spread your legs, and your doctor will insert a metal or plastic tool called a speculum into your vagina,

  1. They’ll open it so that it widens the vaginal walls.
  2. This allows them to see your cervix,
  3. Your doctor will use a swab to take a sample of cells from your cervix.
  4. They’ll place them into a liquid substance in a small jar and send them to a lab for review.
  5. The Pap test doesn’t hurt, but you may feel a little pinch or a bit of pressure.

Your doctor will get them within a few days. They’ll come back either negative (normal) or positive (abnormal). Normal result A negative result is a good thing. That means your doctor didn’t find any precancerous or cancerous cells on your cervix. You won’t need another Pap until you’re due for your next scheduled one.

Mild inflammation or minor cell changes (dysplasia)HPV or other infectionCancer or precancerLab test error

Most often, the abnormal test result means there have been cell changes caused by the human papilloma virus (HPV). That’s the most common sexually transmitted infection (STI), and can be linked to cervical cancer. Changes to your cervical cells caused by HPV can be mild, moderate, or severe.

  • Inflammation can happen if you’ve had sex or used a diaphragm shortly before having a Pap smear.
  • If you have inflammation or minor cell changes, your doctor may take a “wait and see” approach.
  • They may suggest you have another Pap test in a few months.
  • Will I Need More Tests? Your doctor will review your test results and let you know.

Their answer will depend on what type of abnormal cells are found in your cervix. The most common ones are listed below. Atypical squamous cells of undetermined significance (ASCUS). Thin, flat cells called squamous cells grow on the surface of a healthy cervix.

ASCUS occurs when these cells are not typical. Your doctor will do a test with a special liquid to see if HPV is present. If it’s not, there’s probably no need for concern. Squamous intraepithelial lesion. These cells may be precancerous. Doctors call changes to them “low-grade” or “high-grade.” If they’re low-grade, a precancerous cell may not turn to cancer for many years.

If it’s high-grade, the cells could turn to cancer much sooner. Your doctor will likely order more tests, including a colposcopy, an instrument that shows changes in the cervix that may lead to a biopsy of cervical tissue to check for cancerous cells.

Atypical glandular cells. These cells make mucus. They grow in the opening of your cervix and inside your uterus. If they appear to be abnormal, your doctor will order more tests, including a colposcopy, to find out for sure if it’s cancer. Squamous cell cancer or adenocarcinoma cells. This means the cells on your cervix are so abnormal, your doctor is almost certain it’s cancer.

To be sure, your doctor will likely order two other tests: a colposcopy and a biopsy. During a colposcopy, your doctor will insert a speculum into your vagina, just like they did for the Pap test. This time, they’ll look at the cervix with a colposcope.

  1. This is a tool that has a lens and a bright light that allows your doctor to get a better look at your cervix.
  2. They will swab your cervix with vinegar or some other liquid solution.
  3. It’ll highlight any suspicious-looking areas.
  4. Your doctor will be able to see them through the lens on the colposcope.
  5. If your doctor finds areas that don’t look right, they’ll take a sample, called a biopsy.

They’ll send the tissue to a lab for further testing. A Pap smear is considered a safe procedure. But it’s possible that the test may miss some abnormal cells or cervical cancers. This is called a false negative. Talk to your doctor about the benefits and risks of cervical cancer screening.

Does inflammation mean HPV?

7. Chronic inflammation and HPV-induced cancer – Currently there is no more doubt that the persistent infection of the cervical mucosa with high-risk HPV (HR-HPV) is a necessary cause for the development of squamous intraepithelial neoplasia (SIL), low-grade SIL (LSIL) high-grade SIL (HSIL) and invasive cervical cancer (ICC).

  1. However, numerous women are infected with HR-HPV, but the majority of them never develop disease, suggesting that other factors must contribute to the development of the lesions and the transition from premalignant to malignant lesions.
  2. Prior to the discovery of the HPV, infection with C.
  3. Trachomatis and HSV-2 were considered to be major risk factors for the development of ICC.

However, it is now known that this association had probably been mistaken for a long time, due to a lack of methods able to detect the presence of HPV in tumor cells ( 91 ). In past decades, studies have reported an association between chronic inflammation and the occurrence of HSIL and ICC ( 92 – 94 ).

Furthermore, it was demonstrated that in infected females with HR-HPV, the presence of HSIL was highly associated with inflammation. This reinforces the concept that inflammation may be an important cofactor, contributing with HPV in the development of HSIL ( 95, 96 ). Furthermore, was also demonstrated that seminal fluid contains a variety of active molecules, including cytokines, angiogenic factors, proteases, protein kinases, carrier proteins, structural proteins and molecules of the immune response, which are associated with inflammation ( 97 ).

Considering that the development of HSIL and ICC requires an inflammatory environment, it has been proposed that these mediators present in seminal fluid could act to cause inflammation in the cervical mucosa, increasing the risk of lesions. Thus, it is possible that the deposition of seminal fluid in the mucosa of the female genital tract triggers a wave of cytokine release, with the recruitment and activation of leukocytes resulting in inflammation ( 98 ).

  1. This is consistent with previously reported data, which revealed that the use of condoms during sexual intercourse, despite not offering significant protection against genital infection by HPV, significantly reduces the occurrence of lesions in cervical mucosa caused by this virus ( 99 ).
  2. This mucosal protection offered by condoms against HPV infection, is likely due to them preventing contact between the semen and the epithelium of the cervical mucosa.

Notably, Schwebke and Zajackowski ( 93 ) hypothesized that inflammation of the uterine cervix, but not the diagnosis of a specific sexually transmitted disease, is associated with an increased risk of SIL and ICC. However, it is likely that the increased risk of cancer associated with chronic inflammation is due, at least in part, to the presence of infection with other sexually transmitted agents, including HSV-2, C.

Trachomatis and others, that cause an intense local inflammatory response ( 11, 89 ). Various studies have demonstrated that the development of cancer induced by HR-HPV is preceded by chronic long-term inflammation, which in numerous cases, is developed with the participation of other sexually transmissible infectious agents, including HSV-2 and C.

trachomatis ( 81, 82, 100, 101 ). Histological analysis of biopsies of cervical mucosa from HR-HPV-infected females revealed a higher degree of inflammation, with an increased infiltration of lymphocytes and neutrophils into the epithelium, compared with those who were uninfected.

The association between persistent infection with a specific HPV type and progression of LSIL to HSIL was less evident in women with moderate inflammation in the stroma or in the epithelium. In individuals infected with HR-HPV, the inflammation tended to involve only the surface layer of the epithelium, instead of the basal layer, or involvement extended to all the cervical epithelium ( 96 ).

This suggests that inflammation varies with HPV type, persistent or not, and possesses a risk of progression. Assessing the number of macrophages present in the cervical epithelium of healthy females and those with LSIL, HSIL and ICC, Hammes et al ( 96 ) identified a positive linear association between the amount of macrophages and the progression of lesions, finding that an increased migration of macrophages to the epithelium was proportional to the worsening of the injury.

  • A direct association between the amount of macrophages present in the epithelium and the progression of premalignant lesions to cancer was also identified.
  • The intensity of inflammation was also closely associated with the degree of the lesion.
  • The macrophage migration from the epithelium to the stroma was influenced by not only inflammation, but also by the presence of dysplastic cells.

These data reveal that cluster of differentiation (CD)68 + macrophages are associated with cervical carcinogenesis, promoting the progression of intraepithelial lesions to invasive forms. The role of the E6 and E7 HPV16 oncogenes in the regulation of IL-1β expression was analyzed by Niebler et al ( 102 ) in HPV16-immortalized human keratinocytes and in cells obtained from cervical cancer.

These researchers found that in keratinocytes expressing only E7, the secretion of IL-1β was highly inducible by the activation of inflammation; however, in those expressing only E6, no production of IL-1β was detected and the IL-1β precursor and p53 were degraded in a proteasome-dependent manner, mediated by ubiquitin ligase E6-AP.

By contrast, in keratinocytes expressing E6 and E7 or only E7, the levels of the IL-1β precursor were restored by interference RNAs, which block the expression of E6-AP, with simultaneous recovery of functional p53. The results from this study indicated the presence of a novel mechanism for post-translational regulation of the IL-1β precursor that inhibits IL-1β secretion in HPV-infected keratinocytes.

This reveals an effective and innovative mechanism of HR-HPV to prevent the function of IL-1β, which reduces the innate immune response against the infected cells, facilitating persistence of the virus, which is an important step in the initiation of the cell transformation and tumorigenesis ( 102 ).

The systemic levels of proinflammatory cytokines in female patients with persistent HPV infection were evaluated by Kemp et al ( 103 ), who found significantly elevated levels of IL-6, IL-8, TNF-α, macrophage inflammatory protein (MIP)-1α, granulocyte-macrophage colony-stimulating factor, IL-1α and IL-1β in the plasma of the patients with the infection compared with uninfected individuals.

It was also noted that high systemic levels of these cytokines were accompanied by a reduction in lymphoproliferative response. This is a novel finding and is somewhat unexpected as there is little evidence of an HPV-induced systemic inflammatory reaction. The presence of proinflammatory cytokines in the peripheral blood was associated with HPV persistence and weak lymphoproliferative response ( 103 ).

Analyzing the profile of immune response in a case-control study, Peghini et al ( 13 ), found that 75% of individuals with normal cytology exhibited a profile of Th1 cytokines, compared with only 10% of women with LSIL, HSIL or ICC. The samples of ICC exhibited more commonly a Treg profile and behaved in the opposite way to Th1.

  1. Changes in the profile of cytokines present in the microenvironment were also revealed during the progression of lesions, demonstrating a significant reduction of IL-2, IL-12 and TNFα, and an increase in TGFβ with aggravation of the lesions.
  2. The pattern of cytokines found during tumor progression makes it clear that there is involvement of Treg cells in the induction of ICC.

Tumor progression was dependent on the suppression of cellular immunity since normal individuals or individuals with less severe lesions were observed to possess a profile of Th1 cytokines, with a change to an immunosuppressive Treg profile in those with neoplastic progression ( 13 ).

This suggests that a microenvironment with chronic inflammation and an imbalance in the Th1/Treg ratio and the levels of cytokines produced appears to be a critical mechanism for tumor-cell evasion of the immune surveillance system, facilitating tumor progression. The exact mechanism of the clearance of HPV infection remains unclear.

HPV persistence is considered to require a tolerant local immune environment, favoring evasion of the virus or the suppression of the innate and adaptive immune responses ( 103 ). The absence of viremia and cytolysis in cervical HPV infection contributes to the difficulty in defining the immunological mechanisms regulating the clearance of the virus ( 76, 104 ).

It is thought that the innate immune response has a critical role early in the process of healing of HPV infection ( 105 ). Analysis of the signaling of PRRs in uninfected and newly infected keratinocytes, and those persistently infected with HR-HPV, revealed that active infection impairs emission of signals from PRRs to the cell nucleus, affecting the production of type 1 IFNs, proinflammatory cytokines and chemokines.

This mechanism of suppression is dependent on the expression of the intracellular protein ubiquitin carboxyl-terminal L1 (UCHL1), which is induced by HR-HPV in keratinocytes. UCHL1 mediates the degradation of NF-κB and promotes phosphorylation of p65, resulting in the chronic suppression of NF-κB signaling, an important modulator of cellular immunity.

This indicates that HR-HPV uses UCHL1 to escape the innate immunity of the host, by suppressing the production of interferons, cytokines and chemokines induced by PRRs, which are necessary for the attraction and activation of cells that are also involved in the adaptive immune response ( 106 ). Notably, following the integration of HR-HPV into the genome of the host cell, NF-κB appears to go on to have an important role in the development of ICC, since this transcription factor was detected in nucleus and cytoplasm of 96.4% of HPV-positive tumor samples and in only 52.9% of HPV-negative tumor samples.

The overexpression of NF-κB in ICC suggests that NF-κB exerts modulating effects on chronic inflammation and increases the risk of cancer. The mechanism of action of NF-κB in the process of HPV-induced cervical carcinogenesis is probably due to the action of the viral oncoproteins E6 and E7 that, besides increasing the transcriptional activity of NF-κB, eliminate the functions of cellular proteins p53 and pRB, leading to an uncontrolled cell cycle with induction of immortalization and neoplastic transformation of the cell ( 107 ).

  1. It has been demonstrated that E7 induces expression of IL-1β which, in turn, activates the expression of NF-κB, while E6 is associated with the nuclear localization of this transcription factor.
  2. Thus E6 and E7 are associated with the increased activity of NF-κB that is a key modulator in the transition from chronic inflammation to cancer ( 108, 109 ).
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In a recent multiethnic cohort study, Scott et al ( 110 ) monitored females between 2005 and 2010 to evaluate the expression levels of candidate antiviral cytokines in mucosa, including IFN-α2, IFN-γ, IL-12 and IL-10, as well as the proinflammatory cytokines (IL-1α, -1β, -6 and -8, CXCL8, MIP-1α, CCl3 and TNF-α) that are induced following the establishment of HPV infection.

  • The majority of the cohort exhibited increased expression of certain cytokines and decreased expression of others following infection.
  • An association was observed between high levels of IL-10, IL-12, MIP-1α and TNF-α in the cervical mucosa and a reduced likelihood of clearance of any HPV type.
  • For HR-HPV, the trend of no viral clearance was significantly higher in the presence of high levels of IL-12 and TNF-α.

Similar patterns were observed in infection with low-risk HPV, although the trend of not healing was more modest, revealing a significant difference only for IL-10. In the group of women who had rapid healing of HPV infection, low levels of cytokines were associated with a more rapid clearance of the virus, compared with the group of women with established long-term infection.

  • The clearance of HR-HPV was more frequent in the presence of low levels of MIP-1α and IL-8 expression in the cervical mucosa in the group of women that demonstrated rapid healing of infection, but not in the group with established long-term infection.
  • Increased local levels of several important proinflammatory cytokines, including TNFα, MIP-1α, IL-12 and IL-10, were associated with a decreased likelihood of elimination of the virus in women with established long-term infection ( 110 ).

Scott et al made two considerations regarding the results. The first is that in individuals with transient exposure to the virus, in the absence of productive infection, the induction of cytokines may not occur and the virus can be eliminated by a non-immune mechanism.

This would explain the absence of high levels of cytokines among women with rapid clearance of the virus. The second consideration is that, in a successful immune response, the immune mechanisms of homeostatic control may precede the elimination of the virus, bringing the previously high cytokine levels back to baseline levels in anticipation of the elimination of the virus.

There is evidence to support a significant role of TNFα in the immune response against HPV infected cells, as well as in the natural history of disease associated with this virus, since expression of this cytokine by infiltrating mononuclear cells is correlated with spontaneous regression of the lesions induced by HPV.

  • Furthermore, it has been demonstrated that the HPV E6 and E7 proteins suppress the protective effect of TNFα, as E6 induces resistance to TNFα-mediated apoptosis ( 110 ) and E7 inhibits the antiproliferative effect of this cytokine ( 109 ).
  • This suggests that acquisition of resistance to TNFα may be an important step in HPV-induced carcinogenesis.

However, there is also evidence that, under certain conditions, TNFα can act as a tumor promoter ( 111 ). This is an eloquent demonstration of the complexity of the interactions established between the broad spectrum of cytokines produced during the inflammatory response, in which certain cytokines have effects and functions that are occasionally contradictory, depending on the context in which they operate.

  • Persistent infection with HR-HPV results in the integration of viral DNA into the host cell genome and overexpression of oncogenes E6 and E7, which are considered key factors for the development of ICC.
  • These viral genes encode the E6 and E7 oncoproteins, which are responsible for the transforming activity of infected cells.

The main targets of these viral proteins are the cellular tumor suppressor proteins p53 and pRB, which are responsible for cell cycle control ( 112 – 114 ). Though oncogenes E6 and E7 are major HPV genes involved in neoplastic transformation, evidence points to an important role of the E5 viral oncogene in tumorigenesis and in modulation of immune cells ( 115 ).

  • E5 is also involved in the regulation of late viral functions, together with viral gene E4.
  • The E1 and E2 viral genes encode viral replication factors and appear to play a role in HPV persistence, enabling copies of the virus to be maintained in an episomal form in the nucleus and be transferred to daughter cells during mitosis ( 73, 116 ).

Within the epithelial cells, the HPV E6 protein binds to the cellular protein p53 and promotes its degradation by an ubiquitin-dependent pathway, while the HPV E7 protein binds to the pRB family members, consisting of p105, p107 and p130, and promotes their degradation.

The elimination of the functions of p53 and pRB results in uncontrolled cell cycle progression and loss of DNA repair mechanisms, with the consequent accumulation of mutations creating genomic instability ( 72, 73 ). Furthermore, the expression of HPV E6 and E7 genes in differentiating keratinocytes directly alters the expression of genes that influence host resistance to infection and immune functions.

A primary function of E6 and E7 is to maintain the keratinocytes in the cell cycle, but they also prevent antiviral and antitumor effects, and exert immunoregulatory action of the IFN-mediated innate immune system. E7 protein blocks IFN-α activity by inhibiting the expression of the inducible genes that lead to IFN-α production.

  • E7 also inhibits the production of IFN-β by inhibiting the activation of the IFN-β promoter ( 113 ).
  • The changes in cellular functions triggered by the action of viral oncoproteins can also result in increased production of nitric oxide, DNA damage, and activation of cyclooxygenase-2/prostaglandin/prostaglandin receptors (COX2/PGE/PGERs), an inflammatory pathway that leads to increased inflammation and tumorigenesis.

Inflammatory and tumor cells can then release cytokines, chemokines and prostaglandins which act in an autocrine/paracrine manner to regulate the function of endothelial, stromal, neoplastic, epithelial and infiltrating immune cells to cause increased tumor angiogenesis, increased tumor growth, decreased apoptosis and decreased local immune-surveillance.

These conditions favor tumorigenesis and permanence of the virus in the tumor microenvironment. Inhibition of the COX-PGE cascade with nonsteroidal anti-inflammatory drugs such as aspirin could reduce inflammation and tumor progression ( 82, 117 ). The relationship between inflammation, angiogenesis and HPV-induced lesions was assessed by Mazibranda et al ( 12 ), in samples obtained from patients with normal cytology, CIN and ICC.

Based on the density of pan-endothelial cells present on-site, identified by the CD31 marker, a progressive increase in microvessels was observed, with increasing severity of the lesion. Macrophage infiltration was associated with neovascularity in CIN and ICC, with a strong positive correlation between the number of infiltrating macrophages in the tumor and its vasculature.

An increase in macrophages in microvessels was also observed in parallel with neoplastic progression, being even higher in ICC ( 12 ). Immune evasion is an essential aspect of HPV persistence and is also essential for the development of ICC. As there is no sign of viremia, cytolysis or necrosis in the early-phase HPV-infected cervical epithelium, even when it is productive, there is not an adequate activation of the innate immune system or inflammation.

This is due to the fact that the viral E6 and E7 oncoproteins inhibit the expression of PRRs, particularly TLR9, promoting dysregulation of the interferon signaling pathway, preventing activation of the innate immune response and allowing cells to remain infected with HPV, which uses the cellular machinery for viral replication followed by persistence ( 109, 112 ).

Once established, persistent HPV infection leads to changes in the release of proinflammatory cytokines, which in turn may alter the infiltration of immune cells, causing inflammation. Changes in immune response and elevated systemic levels of proinflammatory cytokines have been observed in older women, ~50 years old, with persistent HPV infection ( 111 ).

It was demonstrated that in neoplastic epithelial cells of the cervical mucosa, the E5, E6 and E7 HPV16 oncogenes were able to induce the cyclooxygenase (COX)-prostaglandin inflammatory axis, increasing the immediate expression of the COX2 gene ( 82 ).

These results suggest a direct link between the HPV oncogenes and activation of potent inflammatory cascades with well-known roles in cancer promotion. Thus, although HPV is not associated with inflammation at the initiation of infection, it is likely that, following its integration, persistence and transformation leads to the activation of inflammatory pathways, including the COX-prostaglandin pathway, in neoplastic epithelial cells, promoting immune cell infiltration, inflammation, and tumor progression ( 118 ).

Biopsy studies of tumors associated with HPV reveal significantly higher expression levels of COX1 and COX2 in neoplastic epithelial cells and vascular endothelial cells of all grades and stages in ICC ( 110, 109 ). These findings suggest an important role for the two isoforms of COX in the pathology of disease.

  1. Furthermore, it was revealed that the induction of COX1 expression in HeLa cells, a lineage positive for HPV18, caused a rapid and sustained elevation of COX2 and prostaglandin synthase terminal, resulting in the synthesis of PGE2 ( 109 ).
  2. Furthermore, PGE2 was produced by COX1 and COX2, indicating that they may contribute equally, or act synergistically, to promote ICC ( 118 ).

The mechanism for the selective production of prostaglandin is determined by terminal prostaglandin synthase, which depends on the PTGES synthase enzyme present in COX1- and COX2-expressing cells that converts prostaglandin H2 into PGE2 ( 98 ). It was demonstrated that this enzyme is represented significantly in ICC, and that products of the oncogenes of HPV and PGE2 can regulate the expression of the prostaglandin E receptor PTGER ( 119 ).

  • Furthermore, it was demonstrated that the E5 protein of HPV16 regulates the expression of PTGER4 in the cells obtained from ICC, so that the production of PGE2 is cyclic adenosine monophosphate (cAMP) dependent ( 115 ).
  • These results suggest that increased levels of PGE2 in ICC can regulate the function of neoplastic cells in an autocrine or paracrine manner, through the expression of high levels of the prostaglandin receptors PTGER2 and PTGER4.

There is evidence to indicate that the initial HPV infection is followed by integration of the viral DNA into the genome of the epithelial cells of the cervical mucosa and activation of viral oncogenes, leading to the induction of COX1 and 2 expression, PTGE synthase expression, PGE2 biosynthesis and PTGER expression.

  • In turn, PGE2 can regulate the function of tumor cells through PTGER by the cAMP signaling pathway ( 118 ).
  • Certain immunological parameters were evaluated in women infected with HR-HPV, without lesions, CIN1, CIN3, carcinoma in situ (CIS) and ICC.
  • The results revealed that the cervical mucosa was infiltrated by B cells expressing the CD20 and CD138 markers as early as in CIN1 and this infiltration increased with the worsening of the lesion, being strongly correlated with the infiltration of lymphoid cells expressing the marker CD32B and lymphocytes expressing FoxP3.

The lymphoid cells GATA3 and T-bet were found in greater amounts in samples from patients with ICC compared with those obtained from women with normal cytology. The expression levels of the cytokines thymic stromal lymphopoietin and indoleamine 2,3-dioxygenase-1, promoting Th2 response and serum levels of IL-10, in epithelial cells were higher in the samples from patients with CIN3/CIS and in ICC compared with cytologically-normal samples.

  • An increased infiltration of CD138-, CD20- or CD32B-expressing lymphoid cells into the stroma were observed as early as in CIN1.
  • This indicates that a Th2-type response is present from the first histological evidence of pre-neoplastic transformation caused by HR-HPV.
  • Furthermore, the presence of stromal lymphocytes expressing FoxP3, a marker expressed primarily by Treg cells, was detected in CIN3/CIS and ICC ( 120 ).

In a case-control study, Chen et al ( 33 ) analyzed the cytokine profile and calculated the percentages of Treg and Th17 cells in the peripheral blood of females with normal cytology, CIN1 and ICC. They observed a significant increase in the levels of TGF-β, IL-6, -10, -17 and -23 expression, and lower expression levels of IFN-γ, in patients with CIN1 and ICC compared with those with normal cytology.

These results suggest that the immune response in patients with ICC has been suppressed. It was also observed that the Th17/Treg ratio in the patients with CIN1 and in those with ICC was significantly higher than in the control group. These data suggest that in patients with ICC, the percentage of Th17 and the Th17/Treg ratio were significantly altered.

Also, a positive correlation was found between the percentages of Th17 and expression levels of IL-6, -23 and -17, all of which were higher in patients with ICC. A positive correlation was also found between the percentages of Treg and expression levels of TGF-β and IL-6.

By contrast, there was a negative correlation between the percentage of Treg cells and the expression levels of IFN-γ ( 33 ). These data indicate an imbalance in the TH17/Treg ratio in the peripheral blood of patients with ICC. In a previous study, Zhang et al ( 32 ) had already found the percentage of circulating Th17 and Treg cells to be significantly higher in patients with CIN and ICC compared with a healthy control group.

This study also reported an important imbalance in the average Th17/Treg ratio in patients with CIN or ICC. Furthermore, IL-17 and IL-10 levels were significantly higher in patients with ICC compared with the control group. The levels of Th17 and Treg cells gradually increased during the progression of the disease, leading to an imbalance of the TH17/Treg ratio in patients with ICC, suggesting a potential role of the Th17/Treg imbalance in the progression of CIN to cancer.

Is inflammation of the cervix cancerous?

Inflammatory Response to Deregulation of Vaginal Microbial Environment – As the main defender of the cervicovaginal microenvironment, Lactobacillus maintains the dynamic balance of the entire cervix-vaginal microflora. As mentioned, while the number of Lactobacillus significantly decreased and different anaerobic bacteria gradually dominated, the dynamic balance will be disturbed, leading to the imbalance of cervical and vaginal microorganisms.

Mechanistically, increased microbial diversity leads to the augmented production of related pro-inflammatory cytokines and chemokines, which amplify the inflammatory response and increase the number of immune cells recruited ( Round and Mazmanian, 2009 ; Torcia, 2019 ; Wiik et al., 2019 ; Norenhag et al., 2020 ).

This phenomenon promotes immune dysregulation in the female reproductive tract, thus providing a suitable site for tumor development ( Figure 1 ; Schwabe and Jobin, 2013 ). The mixed microbial infection could promote the replication, transcription and modification of HPV, and increase the incidence of cervical cancer.

Additionally, microbial co-infection could increase inflammation and damage epithelial cells ( So et al., 2020 ), which is one of the mechanisms of cervical intraepithelial neoplasia (CIN) ( Wiik et al., 2019 ; Norenhag et al., 2020 ). Acute inflammation and persistent infection turn into chronic inflammation, which can cause cytotoxic effects on normal cells, damage DNA, and eventually develop into cancer cells, leading to cervical cancer ( Balkwill and Mantovani, 2001 ; Fernandes et al., 2015 ).

The expression of E6 and E7 promoted the inhibition of apoptosis despite the DNA damage in the cells, leading to chromatin abnormalities ( Kyrgiou et al., 2017 ). The microbiota corresponding to the microbiota imbalance of the female reproductive tract and the increase of microbiota diversity is CST-IV, and the female reproductive tract microenvironment dominated by CST-IV is more susceptible than other microbiota.

Active microorganisms in the CST-IV microbiome have become a potential risk factor for the occurrence of cervical cancer ( Champer et al., 2018 ). It is noteworthy that microbial metabolites in the cervix and vagina could also be altered by the phenomenon of microbial disorders ( Ilhan et al., 2019 ).

For example, with the increase of anaerobic or microaerobic bacteria, the metabolites in the female reproductive tract will change from lactic acid to amines ( Nelson et al., 2015 ; Srinivasan et al., 2015 ). Glycochenodeoxycholate (GCDC) is a metabolic product of a host-microbial metabolism, which could inhibit the growth of some anaerobic or microaerobic bacteria usually found in bacterial vaginitis and microbiological disorders ( Fiorucci and Distrutti, 2015 ; Ridlon et al., 2016 ).

However, GCDC can induce inflammation and toxicity, and cause carcinogenesis of the host epithelial cells, when the threshold of GCDC concentration is exceeded ( Tatsugami et al., 2012 ). Ilhan et al. (2019) showed that the concentration of GCDC was elevated with the failure of Lactobacillus and the continuous presence of inflammatory reactions.

All suggest that Lactobacillus is an indispensable guardian of the female reproductive tract. The occurrence of BV and pelvic inflammation (PID) can be influenced by cervicitis ( Klein et al., 2019 ). Cervicitis is usually caused by infection of non-symbiotic microorganisms that express certain antigens, leading to persistent inflammatory infection, as explained previously ( Klein et al., 2020a ).

What is the cellular reaction in inflammation?

Cell types in inflammatory responses – The inflammatory response involves a highly coordinated network of many cell types. Activated macrophages, monocytes, and other cells mediate local responses to tissue damage and infection. At sites of tissue injury, damaged epithelial and endothelial cells release factors that trigger the inflammatory cascade, along with chemokines and growth factors, which attract neutrophils and monocytes.

The first cells attracted to a site of injury are neutrophils, followed by monocytes, lymphocytes (natural killer cells, T cells, and B cells), and mast cells, Monocytes can differentiate into macrophages and dendritic cells and are recruited via chemotaxis into damaged tissues. Inflammation-mediated immune cell alterations are associated with many diseases, including asthma, cancer, chronic inflammatory diseases, atherosclerosis, diabetes, and autoimmune and degenerative diseases.

Neutrophils, which target microorganisms in the body, can also damage host cells and tissues, Neutrophils are key mediators of the inflammatory response, and program antigen presenting cells to activate T cells and release localized factors to attract monocytes and dendritic cells,

Macrophages are important components of the mononuclear phagocyte system, and are critical in inflammation initiation, maintenance, and resolution, During inflammation, macrophages present antigens, undergo phagocytosis, and modulate the immune response by producing cytokines and growth factors. Mast cells, which reside in connective tissue matrices and on epithelial surfaces, are effector cells that initiate inflammatory responses.

Activated mast cell release a variety of inflammatory mediators, including cytokines, chemokines, histamine, proteases, prostaglandins, leukotrienes, and serglycin proteoglycans, Multiple groups have demonstrated that platelets impact inflammatory processes, from atherosclerosis to infection.

What are the cellular signs of inflammation?

Clinical Significance – The signs of inflammation include loss of function, heat, pain, redness, and swelling. Inflammation is part of the body’s complex biological response to harmful stimuli, such as irritants, pathogens, and damaged cells. It is clinically useful to differentiate inflammation and infection as there are many pathological situations where distinguishing them is highly essential to evaluation and treatment.

What is the meaning of cellular inflammation?

Cellular inflammation is an inflammatory process which occurs on a basic, cellular level. Inflammation is a normal process that occurs in the body, and is designed in acute situations, to aid in the healing of tissue.

What happens in the cellular stage of inflammation?

The cellular phase of the inflammatory reaction is characterized by the arrival to the site of inflammation of leukocytes circulating in the blood.