Systemic Effect Of Inflammation

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Systemic Effect Of Inflammation
Systemic inflammation Systemic inflammation Article Talk. Chronic systemic inflammation (SI) is the result of release of pro-inflammatory cytokines from immune-related cells and the chronic activation of the innate immune system. https://en.wikipedia.org › wiki › Systemic_inflammation

Systemic inflammation – Wikipedia

occurs when the immune system is constantly defending the body. Stress, infection, or chronic diseases can put the body in a proinflammatory state. When this happens, the immune system becomes primed and ready to create an inflammatory response.
There are several classic signs of systemic inflammation. They include a fever, headache, fatigue, alterations in CNS, and body aches.

What are examples of systemic inflammatory conditions?

INTRODUCTION – Chronic inflammatory systemic diseases (CIDs) like rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and many others are a burden to humans because of life-long debilitating illness, increased mortality and high costs for therapy and care.

  1. Other than CIDs, infectious disease like influenza or scarlet fever typically last only for a short period of time and they normally do not lead to chronic disease sequelae.
  2. The main difference between CIDs and acute infectious disease is span of time.
  3. While an acute infectious disease or inflammation during wound healing represents an adaptive response to overcome a disease and, thus, to increase life-time reproductive success, a CID is outside the adaptive reaction norm leading to maladaptive responses and a reduction of evolutionary fitness, because the stimulating trigger cannot be removed (for discussion of reaction norm see ).

CIDs are often discussed within the evolutionary medicine framework of the ‘hygiene hypothesis’, This model says that since the start of urbanization humans experienced a depletion of typical environmental infectious organisms such as helminths with which mammals co-evolved.

  1. The loss of these infectious agents provoked a change of normal background levels of immunoregulation during infancy, and this stimulated a more aggressive immune response in adulthood and old age and, thus, more frequent appearance of CIDs,
  2. An approach of evolutionary medicine to CIDs is needed because of the fact that CIDs exist although they exert a negative effect on reproductive fitness,

So far, the persistence of CIDs was partly explained by the important roles a limited number of networked immune system genes play in pathogen defense and other functions that are under strong natural selection, While these previous theories focused on the trigger of CIDs, here we extend this by focusing on common disease pathways and sequelae of CIDs.

  1. Coordinated reactions of the supersystems (immune, nervous, endocrine and reproductive) that maintain homeostasis have been evolutionarily conserved to respond to and eliminate foreign agents over a period of days to a few weeks (e.g.
  2. Influenza or scarlet fever),
  3. If the responses of these supersystems fail to return to normal such as in autoimmunity or other forms of systemic chronic inflammation (e.g.

autoinflammatory syndromes), maladaptation of the supersystems perpetuates long-lasting CIDs, Since 2003 this theory has been refined, because new theoretical concepts from the field of bodily energy regulation were added, This addition improved the model that is presented here in an updated version.

What are systemic causes of inflammation?

Systemic inflammatory response syndrome may be caused by an infection, trauma, surgery, ischemia (lack of blood supply to a part of the body), or certain conditions, such as an autoimmune disorder or pancreatitis.

What are three systemic signs of inflammation?

The signs of inflammation include loss of function, heat, pain, redness, and swelling.

What are the systemic effects?

Systemic means affecting the entire body, rather than a single organ or body part. For example, systemic disorders, such as high blood pressure, or systemic diseases, such as influenza (the flu ), affect the entire body. An infection that is in the bloodstream is called a systemic infection.

An infection that affects only one body part or organ is called a localized infection. Updated by: Linda J. Vorvick, MD, Clinical Professor, Department of Family Medicine, UW Medicine, School of Medicine, University of Washington, Seattle, WA. Also reviewed by David C. Dugdale, MD, Medical Director, Brenda Conaway, Editorial Director, and the A.D.A.M.

Editorial team.

How do you know if you have systemic inflammation?

Body pain – Body pain, such as muscle aches and joint pain, are commonly caused by increased systemic inflammation. When inflammatory cytokines are elevated in the body, they can attack muscle and joint issues resulting in redness, swelling, and pain.

What is the difference between local and systemic inflammation?

The immunological response – A local inflammatory response always occurs in relation to tissue trauma. Local mediators in tissue trauma include kinins and arachidonic acid metabolites. In addition, histamine is released from mast cells in the tissue. These local mediators increase capillary permeability, tissue oedema, and stimulate the local infiltration of immune cells.

While most of these local mediators have a short half life, the effects exerted by these mediators are longer lasting, rendering measurements of the concentration of these mediators in serum unimportant as concentrations of mediators do not necessarily reflect the important local activity. Another endogenous trigger of inflammation is high mobility group box 1 protein (HMGB1).

HMGB1, which is released from necrotic or injured cells, attracts neutrophils and macrophages to the site of injury, increases vascular leakage, and reduces the perfusion pressure in the micro circulation, One of the genetically best preserved non-specific reactions to injury or infection is the complement cascade.

The complement can be activated by three pathways: by antigen-antibody complexes, by bacterial cell wall components, and by the mannan-binding lectin pathway. The split products of the complement activation are able to lyse bacteria directly, opsonise antigens, attract neutrophils and activate platelets.

Activation of the complement system in injury is closely connected to the coagulation cascade. Following trauma, the coagulation system is early and readily activated. It has been demonstrated that thrombin generated in the coagulation cascade activates C5a in the complement system.

  • Activation of the complement system mediates the immune response.
  • In this way the coagulation cascade is connected to the immune system,
  • However, early in trauma it has been difficult to predict the clinical outcome by measuring products of the complement system,
  • Monocytes and endothelium in the area of injury release proinflammatory cytokines of which the most important are IL-1-β, TNF-α, IL-6, IL-8 and IFN-γ (Fig.1 ).

The first cytokines secreted after trauma are TNF-α and IL-1. IL-1 and TNF-α are short lived cytokines and have a similar effect on the immune system. The half life of TNF-α and IL-1 is 20 minutes and 6 minutes respectively, TNF-α and IL-1 stimulate many immunological important cells and are able to induce secretion of proinflammatory cytokines such as IL-6 and IL-8, and the anti-inflammatory cytokine IL-10,

IL-1 also induces a febrile response. IL-6 is first detectable in plasma within an hour after trauma. IL-6 stimulates the hepatic acute phase protein synthesis with release of C-reactive protein (CRP) and procalcitonin. The secretion of IL-6 correlates with the magnitude of the trauma, the duration of surgery and the risk of postoperative complications,

IL-6 has been suggested as a mediator for immune monitoring in the damage control strategy. Figure 1 The proinflammatory response induced by trauma, IL-6 activates neutrophils and NK-cells and inhibits the apoptosis of neutrophils observed following trauma. Although IL-6 functions as a proinflammatory cytokine in the early hours following trauma, it also has an anti-inflammatory effect by promoting the release of IL-1 receptor antagonists and soluble TNF-receptors, IL-6 also induces the production of prostaglandin E2, which stimulates the release of the potent anti-inflammatory cytokine IL-10 (Table 1 ). In this way the initial proinflammatory response following trauma is soon balanced by a compensatory, anti-inflammatory response syndrome. Also induced by IL-1 and TNF-α is the secretion of IL-8. Initially IL-8 attracts initially neutrophils, but later also monocytes lymphocytes and fibroblasts to the area of injury. IL-8 can activate the neutrophils and it prolongs the half life of neutrophils in the area of injury, If the proinflammatory response becomes exaggerated patients might develop SIRS with increased risk of organ dysfunction. On the other hand if the proinflammatory response is repeated, especially in severely ill patients with significant co-morbidities the immune system may become exhausted with increased risk of infection. The initial high concentration of proinflammatory cytokines and acute phase protein measured within the first hours to a few days following major trauma, will gradually normalize and will be balanced by an anti-inflammatory response. If a second peak of acute phase proteins and proinflammatory cytokines is measured in the circulation, complication such as infection should be suspected. Generally there is a strong association between the extent of the tissue injury and the level of cytokines in plasma, while it has been more difficult to demonstrate a correlation between the cytokine response and mortality in trauma patients ” href=”https://localhost/articles/10.1186/1757-7241-17-43#ref-CR31″ id=”ref-link-section-d129739289e712″>31 ]. Table 1 Mediators of the inflammatory response following trauma

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What are systemic inflammatory or autoimmune processes?

Systemic Autoimmune Diseases Systemic autoimmune diseases are a broad range of related diseases characterized by dysregulation of immune system which give rise to activation of immune cells to attack autoantigens and resulted in inappropriate inflammation and multitissue damages.

They are a fascinating but poorly understood group of diseases, ranging from the commonly seen rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) to the relatively rare systemic sclerosis, The mechanism of pathogenesis of systemic autoimmune diseases is still not very clear. It is now considered that genetic factors, infection, endocrine, and environmental exposure are involved in the pathogenesis of these diseases,

There is no treatment strategy to cure this kind of disease at present which gives rise to the needs of long-term lasting treatment, making systemic autoimmune diseases be a mounting public health concern for the foreseeable future. Vital organs such as lung and kidney involvement in systemic autoimmune diseases are common and always presented in a progressive pattern with limited treatment strategy, making them be one of the most common causes of death in patients,

Based on this background, we assembled this special issue for a better understanding of systemic autoimmune diseases, on aspects of mechanisms of pathogenesis, diagnosis, and treatment, including papers ranging from the basic researches to clinical researches and reviews about systemic autoimmune diseases.

Studies on the basic research of systemic autoimmune disease in this issue provided us new insights into the mechanism of the pathogenesis of systemic autoimmune disease. The role of HMGB1 in the T-cell DNA demethylation was discussed in the paper of Y.

Li et al. SNPs with strong RA association signal in the British were analyzed in Han Chinese by H. Li et al., and the methylation status of miR-124a loci in synovial tissues of RA patients was analyzed by Q. Zhou et al. indicating the epigenetic factor in the pathogenesis of RA. Expression of microRNA-155 was studied by L.

Long et al. in RA patients. IL-33 status was tested in RA patients by S. Tang et al.D. Lorton et al. and Y. Du et al. indicated the possible role of beta2-adrenergic receptors ( β 2-AR) and p53 apoptosis effector related to PMP-22(Perp) in the pathogenesis of RA, respectively.

  1. It has long been demonstrated that γδ T cells play important roles in the development of autoimmune diseases; the precise role of γδ T cells in the pathogenesis of SLE was studied by Z.
  2. Lu et al.Z. Gu et al.
  3. Discussed the role of p53/p21 pathway in the pathogenesis of SLE.X.
  4. Gan et al.
  5. Demonstrated the role of GITR and GITRL in the primary Sjögren’s syndrome.

The expression of IL-6 and its clinical significance in patients with dermatomyositis was discussed by M. Yang et al.L. Estrada-Capetillo et al. found that DCs from patients with rheumatic inflammatory disease show an aberrant function that may have an important role in the pathogenesis.S.

  • Stratakis et al.
  • Studied the mechanisms underlying this beneficial effect of rapamycin in passive and active Heymann nephritis (HN).
  • Clinical researches and studies included in this issue provided us several useful clinical clues in the diagnosis, treatment, and prediction of some of systemic autoimmune diseases.L.

Hongyan et al. studied the clinical and pathologic features in lupus nephritis with mainly IgA deposits and made a literature review about this topic. Risk factors for interstitial lung disease in patients with idiopathic inflammatory myopathy were analyzed by X.

Cen et al.J. Chen et al. defined high resolution chest CT (HRCT) and pulmonary function test (PFT) abnormalities capable of identifying asymptomatic, preclinical RA-ILD.L. Pan et al. made a retrospective study to compare the characteristics of connective tissue disease-associated interstitial lung diseases, undifferentiated connective tissue disease-associated interstitial lung diseases, and idiopathic pulmonary fibrosis.

Relationship between Brachial-ankle pulse wave velocity (baPWV) and its associated risk factors in Chinese patients with RA was analyzed by P. Li et al.P. Žigon et al. studied the diagnostic value of antiphosphatidylserine/prothrombin antibodies in systemic autoimmune disease.

The correlations of disease activity, socioeconomic status, quality of life, and depression/anxiety in Chinese SLE patients were studied by B. Shen et al.J. Li et al. made a systematic review on efficacy and safety of Iguratimod for the treatment of rheumatoid arthritis. Review papers also cover many aspects about systemic autoimmune disease.

Advances in the knowledge of costimulatory pathways and their role in SLE were discussed by N.Y. Kow and A. Mak H. Draborg et al. summed up existing data about the relationship between epstein-barr virus and autoimmune disease.T. Marchetti et al. discussed obstetrical antiphospholipid syndrome from pathogenesis to the clinical and therapeutic implications.Y.f.

  • Huang et al.
  • Summarized the immune factors involved in the pathogenesis, diagnosis, and treatment of Sjogren’s syndrome.
  • The role of IL-33 in rheumatic diseases was reviewed by L.
  • Duan et al.T.
  • Ito made a review on advances in the pathogenesis of autoimmune hair loss disease alopecia areata.A.W.J.M.
  • Glaudemans reviewed the use of 18F-FDG-PET/CT for diagnosis and treatment monitoring of inflammatory and infectious diseases.

The role of Fc γ R-mediated trogocytosis in the physiological immune system was discussed by S. Masuda et al.

This special issue covers many important aspects in the systemic autoimmune diseases ranging from novel insights into the pathogenesis of autoimmune disease and the use of newly developed diagnostic strategy in the early diagnosis of autoimmune disease to the treatment of these kinds of diseases, which will surely provide us a better understanding about systemic autoimmune disease. Guixiu  Shi Jianying  Zhang Zhixin  (Jason)  Zhang Xuan  Zhang

1. Cooper GS, Stroehla BC. The epidemiology of autoimmune diseases. Autoimmunity Reviews,2003; 2 (3):119–125.2. Davidson A, Diamond B. Autoimmune diseases. The New England Journal of Medicine,2001; 345 (5):340–350.3. Sen A, Kushnir VA, Barad DH, Gleicher N.

  • Endocrine autoimmune diseases and female infertility.
  • Nature Reviews,2013 4.
  • Rioux JD, Abbas AK.
  • Paths to understanding the genetic basis of autoimmune disease.
  • Nature,2005; 435 (7042):584–589.5.
  • Mimori T, Nakashima R, Hosono Y.
  • Interstitial lung disease in myositis: clinical subsets, biomarkers, and treatment.

Current Rheumatology Reports,2012; 14 (3):264–274. : Systemic Autoimmune Diseases

Can you feel systemic inflammation?

Some of the most common signs of chronic inflammation include: Body discomfort, including joint stiffness, tendonitis and muscle pain. Sleep disorders like insomnia, sleep apnea and persistent fatigue. Weight gain or unexplained weight loss.

What is an example of a systemic effect?

Additional Info – Systemic can refer to a disease, symptom, medication or injury. For example, a bad case of the flu (influenza) affects your entire body. Medications such as aspirin or ibuprofen have anti- inflammatory and analgesic effects throughout the body from your head to your toes.

How do systemic effects occur?

Systemic effects occur at a location distant from the point of contact, i.e., liver, CNS, heart, or kidneys. These effects may occur years after a single high level of exposure, or as the result of chronic exposure.

What is the difference between local and systemic effects?

3.1 Human body – The effects may be immediate or delayed, and they may be reversible or irreversible toxic effects (see Part 1., Introduction to Safety in the Use of Chemicals). Local/systemic toxicity There are two main ways in which chemicals may exert their effects.

Local effects occur at the area of the body which has been in contact with the chemical. Examples are injuries from acids or lung injuries from inhaled reactive gases. Systemic effects occur after the chemical has been absorbed and distributed from the entry point to other parts of the body. Most substances produce systemic effects, but some substances may cause both types of effects.

An example is tetraethyl lead, which is a gasoline additive and produces skin effects at the contact site. It is absorbed and transported into the body causing typical effects on the central nervous system and on other organs. Target organs The degree of the toxic effect is not the same in all organs.

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Usually there are one or two organs which show the major toxic effect. These are referred as target organs of toxicity of the particular substance. The central nervous system is the target organ of toxicity most frequently involved in systemic effects. The blood circulation system, liver, kidneys, lungs and skin follow in frequency of systemic effects.

Muscle and bones are the target organs for a few substances. The male and female reproduction systems are vulnerable to many substances.

  • Skin is the largest organ in the human body, 1.5-2 m 2 in area. It provides a protective cover to the body but can fail if the load is overwhelming. A number of substances can penetrate healthy intact skin and enter the blood circulation. Phenol is a substance that may even result in death after exposure and penetration through the skin. The vast majority of work-related skin diseases are contact eczemas, irritation and inflammation of the skin. This condition can be either a non-allergic or allergic reaction to exposure to chemical substances. Examples of common contact sensitizers are several colorants and dyes, metals such as nickel and its salts, chromium and cobalt salts and organomercuric compounds, monomers of a number of acrylates and methacrylates, rubber additives and pesticides. In practice chemical skin injury is also influenced by environmental conditions such as humidity and heat.
  • The lung is the major route through which toxic substances in the workplace enter the body. It is also the first organ to be affected by dusts, metal fumes, solvent vapours and corrosive gases. Allergic reactions may be caused by substances such as cotton dust, TDI (toluene diisocyanate, used in the manufacture of polyurethane plastics), and MIC (methylisocyanate, used in production of carbaryl insecticide). In a catastrophic chemical accident in Bhopal, India, in 1984, more than 2000 people died from exposure to MIC. Allergic reactions may result from exposure to bacteria or fungi: this is the case in allergies from handling stocked hay (`farmer’s lung’) or dried sugar cane. When dust particles of a certain size of some substances are inhaled the lungs are unable to remove them. They become embedded in the lung causing a condition called pneumoconiosis. Pneumoconiosis is mainly a problem for workers exposed to the dust of silica (quartz) and asbestos, and is the commonest non-malignant occupational lung disease throughout the world. Other substances, such as formaldehyde, sulphur dioxide, nitrogen oxides and acid mists may cause irritation and reduce the breathing capacity.
  • The nervous system, the `mystery of matter and mind’, is sensitive to the hazardous effects of organic solvents. Some metals affect the nervous system, especially heavy metals such as lead, mercury and manganese. Organophosphate insecticides such as malathion and parathion interfere severely with information transmission (chemical neurotransmitter function) in the nervous system, leading to weakness, paralysis and sometimes death.
  • The blood circulation is a target for the adverse effects of solvents. Blood cells are mainly produced in the bone marrow. Benzene affects the bone marrow; the first sign is mutation in the blood cells called lymphocytes. To study mutation, lymphocytes are cultured in the laboratory to observe specific types of cellular changes. Lead, in the form of the metal or its compounds, is another classic example of a chemical that may cause blood problems. Lead in the blood may inhibit certain enzyme activities involved in the production of hemoglobin in red blood cells. Chronic lead poisoning may result in a reduced ability of the blood to distribute oxygen through the body, a condition known as anaemia.
  • The liver is the largest of the internal organs in the body and has several important functions. It is a purification plant which breaks down unwanted substances in the blood. The liver has a considerable reserve capacity; symptoms of liver disorder appear only in serious diseases. Solvents such as carbon tetrachloride, chloroform and vinyl chloride, as well as alcohol, are hazardous to the liver.
  • The kidneys are part of the body’s urinary system. They have the task of excreting the waste products that the blood has transported from various organs of the body, of keeping the fluids in balance and of ensuring that they contain an adequate blend of various necessary salts. They also maintain the acidity of the blood at a constant level. Solvents may irritate and impair kidney function. The most hazardous to the kidneys is carbon tetrachloride. Turpentine in large quantities is also harmful to the kidneys: `painter’s kidney’ is a known condition related to occupational exposure. Other well-known kidney- damaging substances are lead and cadmium.

Allergic reactions An allergic reaction, or sensitization as it is also called, may appear after repeated contact to a substance. Once the sensitization has bee produced, even very low doses can provoke a reaction. The different allergies are numerous, varying from minor skin irritation to very severe or even fatal reactions.

  1. The pattern of sensitization varies according to the species.
  2. In humans, the skin and the eyes are the most common areas of allergic response, whereas, for example, in the guinea pigs reactions are more common in the respiratory system.
  3. Interactions The effect of simultaneous exposure to two or more substances may differ from a simple additive effect (1+1=2).

Organophosphate pesticides, such as dialiphos, naled and parathion, are examples of chemicals where the combined effect is the sum of the effects observed when the chemicals act individually. The effect can be more than the sum of the individual effects of two chemicals (e.g., 1+1=4).

An example of an increase in risk is with asbestos fibres and cigarette smoking. They act together: the risk of developing lung cancer after exposure to asbestos fibres is forty times greater for a smoker than for a non-smoker. Another pair of the chemicals where the combined risk is greater than a mere additive effect are the solvents, trichloroethylene and styrene.

The adverse effects of two substances may counteract one another (1+1=0). This effect is used to find an antidote to a poison. In other cases, a substance may not cause harm on its own but may make the effect of another chemical much worse (0+1=3). For example, two commonly used solvents isopropanol and carbon tetrachloride have this kind of joint effect.

How do I know if I have systemic inflammation?

Evaluation – Tests for Chronic Inflammation Unfortunately, there are no highly effective laboratory measures to assess patients for chronic inflammation and diagnoses are only undertaken when the inflammation occurs in association with another medical condition.

  • Serum protein electrophoresis (SPE) can show concomitant hypoalbuminemia and polyclonal increase in all gamma globulins (polyclonal gammopathy).
  • The two blood tests that are inexpensive and good markers of systemic inflammation include high-sensitivity C-reactive protein (hsCRP) and fibrinogen. High levels of hs-CRP indicate inflammation, but it is not a specific marker for chronic inflammation since it is also elevated in acute inflammation resulting from a recent injury or sickness. The normal serum levels for hsCRP is less than 0.55 mg/L in men and less than 1.0 mg/L in women. The normal levels of fibrinogen are 200 to 300 mg/dl. SAA (Serum Amyloid A) can also mark inflammation but is not a standardized test.
  • Detecting pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta), interleukin-6 (IL-6), and interleukin-8 (IL-8) is an expensive method but may identify specific factors causing chronic inflammation. Again, the assays are not standardized like hs-CRP, fibrinogen, and SPE.

What are the 5 most common signs of inflammation?

Introduction – Based on visual observation, the ancients characterised inflammation by five cardinal signs, namely redness ( rubor ), swelling ( tumour ), heat ( calor ; only applicable to the body’ extremities), pain ( dolor ) and loss of function ( functio laesa ).

The first four of these signs were named by Celsus in ancient Rome (30–38 B.C.) and the last by Galen (A.D 130–200), More recently, inflammation was described as “the succession of changes which occurs in a living tissue when it is injured provided that the injury is not of such a degree as to at once destroy its structure and vitality”, or “the reaction to injury of the living microcirculation and related tissues,

Although, in ancient times inflammation was recognised as being part of the healing process, up to the end of the 19 th century, inflammation was viewed as being an undesirable response that was harmful to the host. However, beginning with the work of Metchnikoff and others in the 19 th century, the contribution of inflammation to the body’s defensive and healing process was recognised,

  1. Furthermore, inflammation is considered the cornerstone of pathology in that the changes observed are indicative of injury and disease.
  2. The classical description of inflammation accounts for the visual changes seen.
  3. Thus, the sensation of heat is caused by the increased movement of blood through dilated vessels into the environmentally cooled extremities, also resulting on the increased redness (due to the additional number of erythrocytes passing through the area).
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The swelling (oedema) is the result of increased passage of fluid from dilated and permeable blood vessels into the surrounding tissues, infiltration of cells into the damaged area, and in prolonged inflammatory responses deposition of connective tissue.

Pain is due to the direct effects of mediators, either from initial damage or that resulting from the inflammatory response itself, and the stretching of sensory nerves due to oedema. The loss of function refers to either simple loss of mobility in a joint, due to the oedema and pain, or to the replacement of functional cells with scar tissue.

Today it is recognised that inflammation is far more complex than might first appear from the simple description given above and is a major response of the immune system to tissue damage and infection, although not all infection gives rise to inflammation.

  • Inflammation is also diverse, ranging from the acute inflammation associated with S.
  • Aureus infection of the skin (the humble boil), through to chronic inflammatory processes resulting in remodeling of the artery wall in atherosclerosis; the bronchial wall in asthma and chronic bronchitis, and the debilitating destruction of the joints associated with rheumatoid arthritis.

These processes involve the major cells of the immune system, including neutrophils, basophils, mast cells, T-cells, B-cells, etc. However, examination of a range of inflammatory lesions demonstrates the presence of specific leukocytes in any given lesion.

That is, the inflammatory process is regulated in such a way as to ensure the appropriate leukocytes are recruited. These events are controlled by a host of extracellular mediators and regulators, including cytokines, growth factors, eicosanoids (prostaglandins, leukotrines, etc), complement and peptides.

In fact, it is the discovery of many of these mediators over the past 20 years that has increased our understanding of the regulation of the inflammatory process whilst, at the same time, revealing its complexity. These extracellular events are matched by equally complex intracellular signalling control mechanisms, with the ability of cells to assemble and disassemble an almost bewildering array of signalling pathways as they move from inactive to dedicated roles within the inflammatory response and site.

  • Which cells and mediators come into play depends on wide range of factors.
  • These include: what stage the process of inflation is at; the initiating event, i.e.
  • Type of pathogen, auto-immune, chemical or physical injury, etc.; the tissue or organ involved; whether the inflammation is of an acute, resolving form or chronic, non resolving or long-lasting type; whether formation of granuloma is involved, or whether scarring results.

The role of inflammation as a healing, restorative process, as well as its aggressive role, is also more widely recognised today. Inflammation is now considered as the full circle of events, from initiation of a response, through the development of the cardinal signs above, to healing and restoration of normal appearance and function of the tissue or organ.

However, in certain conditions there appears to be no resolution and a chronic state of inflammation develops that may last the life of the individual. Such conditions include the inflammatory disorders rheumatoid arthritis, osteoarthritis, inflammatory bowel diseases, retinitis, multiple sclerosis, psoriasis and atherosclerosis.

In order to study inflammation a multidisciplinary approach is necessary. Classically, it has required the study of the immune system, in order to understand the events involved in initiating and maintaining inflammatory conditions. Today it is recognised that the underlying genetics and molecular biology basis to cellular responses are also important in order to identify genetic predisposition to inflammatory diseases, while pharmacological studies are necessary to identify targets and develop novel treatments to bring relief from chronic life-threatening inflammatory conditions.

  • Thus research into inflammation includes not only the study of immunological and cellular responses involved but also the pharmacological process involved in drug development.
  • Many of the drugs used in the treatment of inflammatory conditions, predate our current understanding of the biochemical processes involved in the disease.

Traditionally, the standard treatments for rheumatoid arthritis has been to use a non-steroidal anti-inflammatory drug (NSAID), such as aspirin, for pain relief and to use corticosteroids or even disease-modifying anti-rheumatic drugs in an attempt to reduce other symptoms of the disease.

  1. For many years the pharmaceutical industry attempted to develop NSAIDs which shared the therapeutic action of aspirin but which did not cause the main adverse event, namely gastric ulceration.
  2. This research led to the development of indomethacin, the fenamates, ibuprofen and many others.
  3. However, while all these drugs had clinical utility they also eroded the gastric mucosa.

In addition, this research also led to the development of some of the animal models still used in arthritis research today, such as carrageenin oedema and adjuvant arthritis ). The development of NSAIDs, with reduced potential to cause gastric ulcers, was finally realised with the demonstration that clinically useful NSAIDs inhibited the enzyme cyclo-oxygenase, which was also present in the gastric mucosa.

The finding that cyclo-oxygenase present in inflammatory lesions (COX2) was distinct from that found in the stomach (COX1) led to the development of selective COX2 inhibitors, such as celecoxib. These drugs provide relief from many of the symptoms of arthritis but have a reduced potential to cause gastric ulceration,

The differential responsiveness to these, and other, therapeutic agents and, indeed, the induction of the inflammatory response in some patients with asthma by aspirin, has led to the concept of pharmacogenomics to understand individual drug sensitivities with a view to producing therapy tailored to the individual.

  • Similarly, glucocorticoids are widely used in the treatment of inflammation.
  • Unlike the NSAIDs these agents do not relieve pain but reduce inflammation by inhibiting leukocyte function.
  • The active ingredient responsible for the anti-inflammatory activity of adrenal cortex extracts was discovered in the 1940s.

This led to the use of cortisol as an anti-inflammatory and the development of potent synthetic agents typified by dexamethasone. However, because cortisol, and synthetic glucocorticoids, produce their therapeutic action at supra-physiological concentrations, adverse effects, such as suppression of the HPA-axis and Cushingoid changes are inevitable.

  1. Many of these adverse effects can be avoided by giving glucocorticoids topically.
  2. This has led to the development of inhaled glucocorticoids for the treatment of inflammatory diseases of the respiratory tract and steroid containing creams for the treatment of skin inflammation.
  3. However, applying this approach to the treatment of rheumatoid arthritis necessitates the use of intra-articular injection.

Thus, there is a clear unmet medical need for a drug that provides relief from the symptoms of inflammation but can be given systemically. The fact that a large number of patients with severe chronic inflammatory disease fail to respond to conventional systemic or topical therapy resulting in a huge clinical and socio-economic burdon underlies the need to develop novel therapies.

  • Thus, modern research has used molecular techniques to identify which genes are regulated by glucocorticoid receptors in an attempt to identify novel therapeutic targets.
  • This work has attempted to fine tune the immune system through use of agents that inhibit specific pathways and mediators rather than to suppress immune cell activity.

Examples of such approaches include the development of anti-TNFa therapies, anti adhesion molecule therapies and inhibitors of cytokines believed to be pivotal in a given pathology, Furthermore, inhibitors of selective pro-inflammatory intracellular signalling pathways are currently in use e.g.

cyclsporin or under development e.g. NF-κB, p38 MAPK and PDE4 inhibitors, As we understand more about the complexity of the inflammatory response and the actions of the currently available drugs the value of particular clusters of targets becomes apparent. However, the success of anti-TNFα therapy in RA underlines the importance of understanding/discovering the initial driver(s) of the inflammatory response in individual diseases and patients.

While research into inflammation has resulted in great progress in the latter half of the 20th century, we recognise that the rate of progress is accelerating. Furthermore, it is our perception that there is a need for a vehicle through which this very diverse research can readily be made available to the scientific community.