Chemical Mediators Of Inflammation

29.06.2023 Chukwudi Eze 0 Comments

Mediators – A variety of chemical mediators from circulation system, inflammatory cells, and injured tissue actively contribute to and adjust the inflammatory response, The released chemical mediators include (1) vasoactive amines such as histamine and serotonin, (2) peptide (e.g., bradykinin), and (3) eicosanoids (e.g., thromboxanes, leukotrienes, and prostaglandins).

Contents

0.1 What are the 5 chemical mediators of inflammation?
- 0.1.1 What chemical mediators are activated during inflammation?
0.2 What does chemical mediators of inflammation mean?

1 What are the chemical mediators of inflammation and its classification?
- 1.1 Is histamine a chemical mediator?
2 Do cytokines act as mediators?
3 What are the major chemical mediators?
- - 3.0.1 What are the 5 stages of inflammation?
4 What do histamines and cytokines do?
5 What chemical causes pain in inflammation?
6 Is arachidonic acid a chemical mediator?
7 Are macrophages chemical mediators?
- 7.1 Is histamine excitatory or inhibitory?
8 What are the major chemical mediators?
- - 8.0.1 What are the 5 symptoms of local inflammation?
  - 8.0.2 Is serotonin a chemical mediator?
- 8.1 What are the different chemical mediators for pain?

What are the 5 chemical mediators of inflammation?

Central to the formation of inflammation are the inflammatory mediators, which include proteins, peptides, glycoproteins, cytokines, arachidonic acid metabolites (prostaglandins and leukotrienes), nitric oxide, and oxygen free radicals.

What chemical mediators are activated during inflammation?

Chemical mediators of inflammation One of the best-known chemical mediators released from cells during inflammation is histamine, which triggers vasodilation and increases vascular permeability. Stored in granules of circulating basophils and mast cells, histamine is released immediately when these cells are injured.

What does chemical mediators of inflammation mean?

THIS BRIEF review will cover only some of the important aspects of the subject but will try to define an outline from which one can gain a reasonable concept of current knowledge and proceed to further detailed investigation if he desires. One is also directed to recent detailed reviews 1-3 which should be of considerable interest.

From the time of the original stimulus (heat, ultraviolet, toxins, antigens, trauma, etc) to the restitution of normal function there is a very complicated, and for the most part unknown, series of humoral and cellular events described by the ancient term, inflammation. A mediator may be defined as an endogenous chemical agent which takes an active part in the development of the inflammatory response.

We are then concerned primarily with chemical (mediator) agents which are associated with and responsible for the events occurring during inflammation. Exogenous agents which induce inflammatory responses are not

What are the chemical mediators of inflammation and its classification?

Synthetic/Semisynthetic Flavonoid Derivatives With Antiinflammatory Activity – Acute and/or chronic inflammation can be controlled by chemical mediators, such as cytokines, chemokines, histamine, serotonin, and eicosanoids. Tumor necrosis factor-α (TNF-α) is a cytokine that activates nuclear factor-κB (NFκB), one of the central transcription factors in inflammatory processes.

NF-κB activation promotes the transcription of certain genes encoding for the synthesis of new cytokines, chemokines, and proinflammatory enzymes, including cyclooxygenase (COX)-1 and COX-2, 5-lipoxygenase (5-LOX), and inducible nitric oxide synthase (iNOS). COX-2, 5-LOX, and iNOS control the biosynthesis of crucial proinflammatory mediators (prostaglandins, prostacyclin and thromboxane, leukotrienes, and nitric oxide (NO), respectively), which may lead to such symptoms of inflammation as vasoconstriction or dilation, vasopermeability, coagulation, pain, and fever.

Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit COX-1 and COX-2, the latter especially. TNF-α also interacts with other crucial cellular processes mediated or promoted by cyclin-dependent kinases (CDKs), MAPKs, activator protein-1 (AP-1), the apoptotic pathways, etc.

Long-term therapy with NSAIDs increases the risk of gastrointestinal and cardiovascular complications, which has increased interest in developing new antiinflammatory drugs that are safer for long-term use. Flavonoid derivatives have been synthesized with the intention of improving several effects of their natural analogues: direct interaction with proinflammatory proteins, inhibition of the expression of inflammation-related genes, and antioxidant and prooxidant effects,

Some derivatives have been demonstrated to interact with proinflammatory mediators either directly or via inhibition of their expression within cells. For example, chalcone derivatives containing aryl-piperazine or aryl-sulfonyl-piperazine moieties ( Fig.2.26 ) inhibited the expression of cytokines IL-6 and TNF-α by RAW264.7 macrophages, with better outcomes obtained for the latter series of compounds.

Preliminary SAR analysis indicated that the presence of a sulfonyl group and the introduction of an electron-withdrawing group at the 4-position of aryl-piperazine or aryl-sulfonyl-piperazine moieties improved antiinflammatory activity.
On the other hand, the addition of various substituents at the 4′-position of the benzene ring was found to be unfavorable for antiinflammatory activity,

Furthermore, flavone derivatives with the general structures of 6-methoxy-2-(piperazin-1-yl)-4H-chromen-4-one and 5,7-dimethoxy-2-(piperazin-1-ylmethyl)-4H-chromen-4-one demonstrated good in vitro inhibitory activity against TNF-α and IL-6. Most of the active compounds were found to be equally or more potent than the standard dexamethasone at 1 μM, with compounds of the second series being more active than those of the first. CN) on the piperazine group had the opposite effect. As a result, the derivative-bearing pyrimidyl group bound to the piperazine ring was found to be the most active member of this series, Fig.2.26, General structure of chalcone derivatives containing aryl-piperazine or aryl-sulfonyl-piperazine moieties, Dihydroquercetin Mannich condensation products ( Fig.2.27 ) have been shown to inhibit the expression of collagenase 1 (MMP-1) in human dermal fibroblasts more potently than retinoic acid, used as the reference drug, but showed no notable activity in IL-8 experiments, Fig.2.27, Dihydroquercetin and its derivatives for MMP-1 and IL-8 tests, In addition, a series of minor prenylated flavonoid derivatives has been found to inhibit prostaglandin E 2 (PGE 2 ) secretion by LPS-induced murine RAW 264.7 macrophages in a moderate to strong manner (41%–90%).

Docking studies predicted that the most active compound of the series ( Fig.2.28 ), a prenylated chalcone, would have a high binding affinity toward COX-2. The prenyl substituent appears to be crucial, establishing key interactions with the hydrophobic pocket in the active site of COX-2. However, in silico studies revealed the potential hepatotoxicity of this compound,

A new macakurzin C derivative, CPD 14 ( Fig.2.29 ), inhibited the release of inflammatory mediators in LPS-induced murine macrophages and IFN-γ/TNF-α-induced human keratinocytes. NF-κB and the nuclear erythroid 2-related factor/heme oxygenase-1 (Nrf2/HO-1)-signaling pathways were found to be responsible for the antiinflammatory effects of CPD 14. OH of C-7, bound to various heterocyclic groups ( Fig.2.30 ), exhibited potent COX-2 inhibition and increased selectivity over COX-1 in vitro and antiinflammatory activity in vivo. In contrast, corresponding natural flavonoids were found to be inactive; compounds bearing benzimidazole terminal moieties were found to be more active than those with six- or five-membered heterocyclic groups. Fig.2.28, (3,4-Dimethoxyphenyl)-1-(2-hydroxy-4-methoxy-5-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one, Fig.2.29, Macakurzin C derivative CPD14, Fig.2.30, (A) General structures of 2-(4-oxo-2-phenyl-4H-chromen-7-yloxy)acetamides with heterocyclic substituents and (B) structure of the most active compound of the series, Several other flavonoid derivatives have been tested in different animal inflammation models.

A series of chalcone derivatives containing aminoguanidine or acylhydrazone moieties have been reported to manifest antiinflammatory properties in a xylene-induced ear edema model in mice. They demonstrated a high level of inhibition against edema formation (92.45%), higher than that obtained under similar conditions for the reference drugs indomethacin and ibuprofen,

A flavone derivative, DA-6034 (7-carboxymethoxy-3′,4′,5-trimethoxy flavone), was tested on inflammatory bowel disease (IBD) models in rats. Oral therapy with DA-6034 attenuated macroscopic and histologic damage of the colon, demonstrating more potent activity than prednisolone and sulfasalazine, the reference drugs, in terms of macroscopic lesion score,

The O-alkyl and O-acyl groups of 5-hydroxyflavonoid derivatives exhibited in vivo inhibitory activity against carrageenan-induced paw edema in mice; the most active compounds demonstrated greater antiinflammatory activity than the standards (diclofenac and ketoprofen),
Indomethacin–naringenin and indomethacin–hesperetin hybrid structures were also considered potentially safer alternatives to NSAID treatment.

These derivatives displayed potential antiinflammatory and analgesic activity with significantly reduced gastric side effects than equivalent mixtures of the free compounds, Polymorphonuclear neutrophils generate ROS (mainly superoxide anion, O 2 · − ) during macrophage phagocytosis and in reply to various stimuli.

Such a functional response, termed an oxidative burst, contributes to host defense mechanisms, but it can also result in injuries to cell tissues, causing an inflammatory response,
Inflammation resolution therefore depends on the extent of abnormal neutrophil superoxide production, which as a consequence represents an attractive target for the development of novel antiinflammatory agents.

As a result, another approach to developing new flavonoid derivatives with antiinflammatory activity aims at improving the antioxidant properties of natural flavonoids. Hence, several chlorinated flavone derivatives, intended to mimic the chlorinated metabolites of flavonoids, have been found to be more efficient than their parent compounds (flavone, luteolin, quercetin) at modulating neutrophil oxidative bursts by inducing neutrophil apoptosis in a caspase 3-dependent manner.8-Chloro-3′,4′,5,7-tetrahydroxyflavone demonstrated the highest inhibitory activity against neutrophil oxidative bursts,

Is histamine a chemical mediator?

2. Histamine and Histamine Receptors – Histamine (2-ethanamine) is an important chemical mediator that causes vasodilation and increased vascular permeability and may even contribute to anaphylactic reactions, It also acts on several physiological functions, such as cell differentiation, proliferation, haematopoiesis, and cell regeneration.

Synthesis of histamine occurs through decarboxylation of the amino acid histidine by the enzyme L-histidine decarboxylase (HDC), which is expressed in neurons, parietal cells, gastric mucosal cells, mast cells, and basophils; degradation of histamine is mediated by the enzyme diamine oxidase (DAO) and histamine N-methyltransferase (HNMT), which catalyses histamine deamination,

HNMT is expressed in the central nervous system, where it may play a critical regulatory role because its deficiency is related to aggressive behaviour and abnormal sleep-wake cycles in mice, The pleiotropic effects of histamine are mediated by 4 histamine receptors (HRs), H1R, H2R, H3R, and H4R, which are G protein-coupled receptors.

The active and inactive conformations of these receptors coexist in equilibrium. Agonists of these receptors stabilize the active conformation, whereas antagonists stabilize the inactive conformation. Curiously, the ageing process impairs expression or activity of HRs, and the enzymes HDC and DAO may contribute to the progression of allergic reactions and various neurodegenerative disorders,

Chronic itch in the elderly is a common problem that is often multifactorial due to physiological changes in ageing skin, including impaired skin barrier function, and changes in immunological, neurological, and psychological systems associated with age.

H1R is expressed in various cell types, such as neurons, endothelial cells, adrenal medulla, muscle cells, hepatocytes, chondrocytes, monocytes, neutrophils, eosinophils, DCs, T cells, and B cells.
H1R signaling results in the following: synthesis of prostacyclins; activation of platelet factor; synthesis of nitric oxide, arachidonic acid and its metabolites, and thromboxane; and contraction of smooth muscle cells.

In addition, H1R activation leads to increased chemotaxis of eosinophils and neutrophils at the site of inflammation, higher functional capacity of antigen-presenting cells (APCs), activation of Th1 lymphocytes, and decreased humoral immunity but the promotion of IgE production,

As expected for such biological actions, H1R antagonists, including pyrilamine, fexofenadine, diphenhydramine, and promethazine, are commonly used for the treatment of allergic symptoms. Signaling via H1R leads to the activation of intracellular transcription factors, such as IP3 (inositol triphosphate), PLC (phospholipase C), PKC (protein kinase C), DAG (diacylglycerol), and Ca 2+,

Recently, H1R and H4R signaling was implicated in MAPK signaling and cAMP accumulation, leading to increased proinflammatory gene expression, In addition, activation of H1R is important for the generation of Th1 responses, whereas H2R regulates Th2 responses.

Mice genetically deficient for H1R (H1R−/−) have an exacerbated Th2 profile due to a decrease in Th1 responses, In addition, H1R was demonstrated in an experimental allergy model to play a critical role together with histamine in orchestrating recruitment of Th2 cells to the site of allergic lung inflammation,

H2R is expressed by parietal cells of the gastric mucosa, muscle, epithelial, endothelial, neuronal, hepatocyte, and immune cells. H2R antagonizes some of the effects mediated by H1R and leads to the relaxation of smooth muscle cells, causing vasodilation.

H2R activation regulates several of the functions mediated by histamine, including cardiac contraction, gastric acid secretion, cell proliferation, and differentiation, It also acts as a suppressor molecule in DCs, increasing IL-10 production, One recent study demonstrated that histamine acts on H2R and induces inhibition of leukotriene synthesis in human neutrophils through cAMP-dependent protein kinase (PKA) signaling,

In a murine lung inflammation model, H2R loss has an effect on invariant natural killer T (iNKT) cells, aggravating local inflammation, In monocyte-derived DCs from healthy adult subjects, H2R activation counterbalances the Toll-like receptor (TLR) response, leading to inhibition of CXCL10, IL-12, and TNF- α stimulation of IL-10, which is likely associated with Th2 polarization,

Mechanistically, inhibition of TLR-associated NF- κ B and AP-1 pathways occurs due to cAMP activation downstream of H2R activation, While the activation H1R and H2R mainly accounts for mast cell- and basophil-mediated allergic disorders, H3R functions were identified in the central nervous system and peripheral and presynaptic receptors to control the release of histamine and other neurotransmitters.

The asymmetry of histamine via H3R inhibits the acetylcholine released in the mouse cortex, which controls neurogenic inflammation by inhibiting cAMP formation and Ca 2+ accumulation, H3R knockout mice exhibit an obese phenotype, suggesting that H3R regulates insulin resistance and leptin release, as well as a decrease in homeostatic energy, the cellular process for coordinating homeostatic regulation of food intake (energy inflow) and energy expenditure (energy outflow), as associated with the UCP1 and UCP3 genes,

H3R expression may be associated with bronchoconstriction, pruritus (without involvement of mast cells), increased proinflammatory activity, and antigen-presentation capacity, Neuromodulation and the waking state are related to histaminergic neurons. The waking state is maintained by continual activation of aminergics (such as histamine, dopamine, noradrenaline, and acetylcholine).

Three subtypes of HRs are widely distributed in the brain, not only on neurons but also on astrocytes and blood vessels. Positive-allosteric modulators of GABA A receptors acting on histamine neurons in the posterior hypothalamus induce a natural NREM-like sleep,

Targeting the histamine and noradrenergic systems may aid in the design of more precise sedatives and, at the same time, may reveal more about the natural sleep-wake circuitry, In fact, there is a potential utility of histamine H3R antagonist/inverse agonists for CNS disorders. An experimental study showed that when subjected to lipopolysaccharide (LPS) challenge, histamine inhibits the injurious effect of microglia-mediated inflammation by protecting dopaminergic neurons, highlighting the down-modulatory ability of histamine and/or HR agonists.

This finding may be useful for the development of new therapeutic approaches to treat neurodegenerative disorders, H4R is preferentially expressed in the intestine, spleen, thymus, bone marrow, peripheral haematopoietic cells, and cells of the innate and adaptive immune systems.

Expression of H4R is regulated by stimulation with IFN, TNF- α, IL-6, IL-10, and IL-13, leading to inhibition of cAMP accumulation and activation of MAPK (mitogen-activated protein kinases) by H4R.
Activation of this receptor causes chemotaxis in mast cells and eosinophils, leading to an accumulation of inflammatory cells and control of cytokine secretion by DC and T cells.

H4R is also involved in increased secretion of IL-31 by Th2 cells, Treatment of mice with the H4R antagonist JNJ7777120 attenuates pruritus in response to histamine, IgE, and compound 48/80, and its inhibitory effect is greater than that observed with H1R antagonists,

The use of this synthetic H4R antagonist in a murine encephalomyelitis model resulted in an increase in the clinical and pathological signs of the disease, suggesting a modulatory role, HRs are present on tumour cells, making them sensitive to variations in histamine. High levels of histamine are associated with bivalent behaviour in the regulation of several tumours (i.e., cervical, ovarian, vaginal, uterine, vulvar, colorectal, and melanoma cancers) by promoting or inhibiting their growth,

The presence of H3R and H4R in human mammary tissue suggests that H3R may be involved in regulating breast cancer growth and progression, emphasizing the possible use of antihistamines as adjuvants in cancer chemotherapy. In HDC-deficient mice, a decrease in H4R expression on iNKT cells is associated with lower production of IL-4 and IFN- γ by those cells, which demonstrates regulation between these factors,

Several studies have shown that histamine is involved in regulating the function of DCs, such as by potentiating antigen endocytosis, inducing intracellular Ca 2+ mobilization, promoting F-actin polymerization in immature DCs derived from monocytes, and promoting expression of MHC class II molecules.

Strikingly, cross-presentation, the ability to drive MHC II-associated antigens towards the MHC I pathway, is blocked by H3R/H4R antagonists. Histamine also acts on T cell polarization by inhibiting IFN- γ or LPS-driven IL-12 production in a H1R/H2R dependent manner,

H4R has a modulatory role in APCs (DCs and monocytes) by exerting anti-inflammatory action and reducing IL-12 and CCL2 production,
Asthma is prevalent in males during childhood but is more frequent in females during adolescence and adulthood.
Furthermore, allergic diseases are common in women of childbearing age.

Both asthma and atopic conditions may worsen, improve, or remain the same during pregnancy. Female hormones, such as estrogen, can modulate the inflammatory response, and histamine receptors can differ between males and females, which might explain the different incidence of allergy between the sexes, Intracellular activation cascades triggered by histamine receptors (HRs). The pleiotropic effects of histamine are mediated by four histamine receptors: H1R, H2R, H3R, and H4R, which are G protein-coupled receptors. Signaling via H1R leads to activation of intracellular transcription factors, such as PLC (phospholipase C), IP3 (inositol triphosphate), PKC (protein kinase C), DAG (diacylglycerol), and Ca 2+,

Do cytokines act as mediators?

1 Introduction – Cytokines are the mediators of the immune system. They are small proteins of around 25 kD that are produced in response to a stimulus (ie, invading microbes) by numerous cell types. They mediate and regulate immune responses, inflammatory reactions, wound healing, hematopoiesis, and chemotaxis, and can be divided into being proinflammatory or antiinflammatory.

Their mechanism of action is via specific receptors and can either be autocrine (ie, on themselves), paracrine (ie, on cells in the vicinity), or endocrine (ie, spread via circulation to distant sites). Originally, they were named according to their functionality after either the cell type producing them (monokine and lymphokine) or the cell they acted upon,

Cytokines can be divided into chemokines, interferons (IFNs), ILs, some colony-stimulating factors, and tumor necrosis factor (TNF). Chemokines are a certain subclass of cytokines. Approximately 50 different chemokines have been described so far, and they function as chemo-attractants, inducing cells recognizing them to migrate along the chemokine gradient.

They determine, for example, the specific localization of lymphocytes and dendritic cells (DCs) in peripheral lymphoid organs. Chemokines can be divided into two different subclasses: CC chemokines with two neighboring cysteine residues close to the amino terminus, and CXC chemokines with two cysteine residues separated by another amino acid.

CC chemokines are recognized by CC receptors (CCRs), whereas CXC chemokines are recognized by CXC receptor (CXCR) molecules. In contrast to hormones, which are present at very low concentrations and are produced by specific cells, cytokines are present at higher (some even picomolar) concentrations that can under certain circumstances increase dramatically.

Moreover, a given cytokine can be secreted by several different cells, and several cytokines may act in similar ways, resulting in a certain redundancy of the system.
In addition, one cytokine may affect different cell types in different ways (pleiotropy).
In most cases, there is not a single cytokine present, but multiple different ones acting either additively, synergistically or antagonistically to each other, leading to a complexity in the system that is difficult to analyze in in vitro systems.

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The innate immune system is considered to be fast but rather nonspecific. It comprises physical barriers, such as epithelia, soluble molecules such as complement, and cellular components, such as leukocytes. Besides neutrophils, macrophages, DCs and natural killer (NK) cells, also the recently identified innate lymphoid cells (ILCs) possess important regulatory and effector functions in immunity and homeostasis.1 Pathogens and tissue damage are detected by innate immune cells via pattern recognition receptors (PRRs).

What are the major chemical mediators?

Included among these mediators are arachidonic acid derivatives (leukotrienes and prostaglandins), vasoactive peptides (kinins), phospholipid mediators (platelet activating factor), and cytokines (interleukins and other bioresponse modifiers).

What are the 5 stages 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,

Furthermore, inflammation is considered the cornerstone of pathology in that the changes observed are indicative of injury and disease.
The classical description of inflammation accounts for the visual changes seen.
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).

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.

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. This research led to the development of indomethacin, the fenamates, ibuprofen and many others. 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.

Many of these adverse effects can be avoided by giving glucocorticoids topically.
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.
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.

What do histamines and cytokines do?

Table 1 – Types and functions of different histamine receptors.


	Expression in Cell Types	Function	Available studies in relation to COVID-19
Histamine 1 Receptor (H1R)	neurons, endothelial cells, adrenal medulla, muscle cells, hepatocytes, chondrocytes, monocytes, neutrophils, eosinophils, dendritic cells (DCs), T cells, and B cells	• activation of Th1 lymphocytes, and decreased humoral immunity	• none
Histamine 2 Receptor (H2R)	parietal cells of the gastric mucosa, muscle, epithelial, endothelial, neuronal, hepatocyte, and immune cells	• antagonizes some of the effects mediated by H1R and leads to the relaxation of smooth muscle cells, causing vasodilation. • inhibition of CXCL10, IL-12, and TNF-α stimulation of IL-10, which is likely associated with Th2 polarization	• Observational studies,, ] • Multi-site Adaptive Trials
Histamine 3 Receptor (H3R)	identified in the central nervous system and peripheral and presynaptic receptors	• control the release of histamine and other neurotransmitters	• none
Histamine 4 Receptor (H4R)	preferentially expressed in the intestine, spleen, thymus, bone marrow, peripheral hematopoietic cells, and cells of the innate and adaptive immune systems.	• Activation causes chemotaxis in mast cells and eosinophils, leading to accumulation of inflammatory cells and control of cytokine secretion • increased secretion of IL-31 by Th2 cells	• none

H3R functions were identified in the central nervous system and peripheral and presynaptic receptors to control the release of histamine and other neurotransmitters. H4R is preferentially expressed in the intestine, spleen, thymus, bone marrow, peripheral hematopoietic cells, and cells of the innate and adaptive immune systems.

Expression of H4R is regulated by stimulation with TNF-α, IL-6, IL-10, and IL-13, leading to inhibition of cAMP accumulation and activation of mitogen-activated protein kinases (MAPK) by H4R.
So histamine is a potent inflammatory mediator, commonly associated with allergic reactions, promoting vascular and tissue changes and possessing high chemoattractant activity.

The use of selective H4R ligands and/or modulation of H1 and H4 receptor synergism may be more effective in the treatment of inflammatory conditions of the lung. Histamine also modulates the inflammatory response by acting on other cellular populations, in human lung macrophages.

The binding of histamine to H1R induces production of proinflammatory cytokine IL-6 and β-glucuronidase.
Blocking H4R in a model of pulmonary fibrosis alleviates the inflammatory response, reducing Cyclooxygenase 2 (COX 2) expression and activity, leukocyte infiltration, production of Transforming growth factor beta (TGF-β) (profibrotic cytokine), and collagen deposition.

At the present, there are few studies looking into the use of antihistamine products in patients with COVID-19. In self-administered high dose oral famotidine therapy, all 10 patients had marked improvements of COVID-19 symptoms, Interestingly, analysis of pharmacokinetic parameters of famotidine might indicate that it needs to be given intravenously to be effective in COVID-19 treatment given its low gastrointestinal absorption and volume of distribution,

In a propensity-score matched retrospective cohort study comparing famotidine cohort (84 patients) to non-famotidine cohort (1536 patients), a crude analysis showed that famotidine use was significantly associated with reduced risk for death and was independently associated with risk for death or intubation (adjusted hazard ratio (aHR) 0.42, 95% CI 0.21–0.85),

The famotidine group received between 10 and 40 mg/day for a median of 5.8 days, and 72% received it orally, One limitation to recognize is the risk of unmeasured confounders, particularly that sicker patients might be more likely to receive proton-pump inhibitors than H2R blockers.

Although famotidine is an H2R antagonist and used mainly for peptic ulcer and gastroesophageal reflux, its potential benefit was attributed to binding and inhibiting the 3-chymotrypsin-like protease, There is currently one ongoing double-blind randomized controlled trial in New York evaluating the efficacy of high dose intravenous famotidine (360 mg/day) with standard of care for a maximum of 14 days in hospitalized COVID-19 patients,

The H2R antagonists class also includes ranitidine cimetidine, and nizatidine. In allergic reactions, the preferred antihistamines target H1R, Currently, we could not find studies evaluating the efficacy of H1R blockers in COVID-19. Histamine is a main mediator that is being released by immune system and other cells as a result of virus invasions or activation.

Is serotonin a chemical mediator?

Professional Version Topic Resources Biochemical mediators released during inflammation intensify and propagate the inflammatory response ( See table: Actions of Inflammatory Mediators Actions of Inflammatory Mediators ). These mediators are soluble, diffusible molecules that can act locally and systemically. Mediators derived from plasma include complement and complement-derived peptides and kinins. Released via the classic or alternative pathways of the complement cascade, complement-derived peptides (C3a, C3b, and C5a) increase vascular permeability, cause smooth muscle contraction, activate leukocytes, and induce mast-cell degranulation.

C5a is a potent chemotactic factor for neutrophils and mononuclear phagocytes.
The kinins are also important inflammatory mediators.
The most important kinin is bradykinin, which increases vascular permeability and vasodilation and, importantly, activates phospholipase A 2 (PLA 2 ) to liberate arachidonic acid (AA).

Bradykinin is also a major mediator involved in the pain response. Other mediators are derived from injured tissue cells or leukocytes recruited to the site of inflammation. Mast cells, platelets, and basophils produce the vasoactive amines serotonin and histamine. Histamine causes arteriolar dilation, increased capillary permeability, contraction of nonvascular smooth muscle, and eosinophil chemotaxis and can stimulate nociceptors responsible for the pain response.

Its release is stimulated by the complement components C3a and C5a and by lysosomal proteins released from neutrophils. Histamine activity is mediated through the activation of one of four specific histamine receptors, designated H 1, H 2, H 3, or H 4, in target cells. Most histamine-induced vascular effects are mediated by H 1 receptors.

H 2 receptors mediate some vascular effects but are more important for their role in histamine-induced gastric secretion. Less is understood about the role of H 3 receptors, which may be localized to the CNS. H 4 receptors are located on cells of hematopoietic origin, and H 4 antagonists are promising drug candidates to treat inflammatory conditions involving mast cells and eosinophils (allergic conditions).

Serotonin (5-hydroxytryptamine) is a vasoactive mediator similar to histamine found in mast cells and platelets in the gastrointestinal tract and the CNS. Serotonin also increases vascular permeability, dilates capillaries, and causes contraction of nonvascular smooth muscle. In some species, including rodents and domestic ruminants, serotonin may be the predominant vasoactive amine.

Cytokines, including interleukins 1–10, tumor necrosis factor alpha (TNF-alpha), and interferon gamma (INF-gamma) are produced predominantly by macrophages and lymphocytes but can be synthesized by other cell types as well. Their role in inflammation is complex.

These polypeptides modulate the activity and function of other cells to coordinate and control the inflammatory response.
Two of the more important cytokines, interleukin-1 (IL-1) and TNF-alpha, mobilize and activate leukocytes, enhance proliferation of B and T cells and natural killer cell cytotoxicity, and are involved in the biologic response to endotoxins.

IL-1, IL-6, and TNF-alpha mediate the acute phase response and pyrexia that may accompany infection and can induce systemic clinical signs, including sleep and anorexia. In the acute phase response, interleukins stimulate the liver to synthesize acute-phase proteins, including complement components, coagulation factors, protease inhibitors, and metal-binding proteins.

By increasing intracellular Ca 2+ concentrations in leukocytes, cytokines are also important in the induction of PLA 2, Colony-stimulating factors (GM-CSF, G-CSF, and M-CSF) are cytokines that promote expansion of neutrophil, eosinophil, and macrophage colonies in bone marrow. In chronic inflammation, cytokines IL-1, IL-6, and TNF-alpha contribute to the activation of fibroblasts and osteoblasts and to the release of enzymes such as collagenase and stromelysin that can cause cartilage and bone resorption.

Experimental evidence also suggests that cytokines stimulate synovial cells and chondrocytes to release pain-inducing mediators. Lipid-derived autacoids play important roles in the inflammatory response and are a major focus of research into new anti-inflammatory drugs.

These compounds include the eicosanoids such as prostaglandins, prostacyclin, leukotrienes, and thromboxane A and the modified phospholipids such as platelet activating factor (PAF).
Eicosanoids are synthesized from 20-carbon polyunsaturated fatty acids by many cells, including activated leukocytes, mast cells, and platelets and are therefore widely distributed.

Hormones and other inflammatory mediators (TNF-alpha, bradykinin) stimulate eicosanoid production either by direct activation of PLA 2, or indirectly by increasing intracellular Ca 2+ concentrations, which in turn activate the enzyme. Cell membrane damage can also cause an increase in intracellular Ca 2+,

Activated PLA 2 directly hydrolyzes AA, which is rapidly metabolized via one of two enzyme pathways—the cyclooxygenase (COX) pathway leading to the formation of prostaglandin and thromboxanes, or the 5-lipoxygenase (5-LOX) pathway that produces the leukotrienes. Cyclooxygenase catalyzes the oxygenation of AA to form the cyclic endoperoxide PGG 2, which is converted to the closely related PGH 2,

Both PGG 2 and PGH 2 are inherently unstable and rapidly converted to various prostaglandins, thromboxane A 2 (TXA 2 ), and prostacyclin (PGI 1 ). In the vascular beds of most animals, PGE 1, PGE 2, and PGI 1 are potent arteriolar dilators and enhance the effects of other mediators by increasing small-vein permeability.

Other prostaglandins, including PGF2alpha and thromboxane, cause smooth muscle contraction and vasoconstriction. Prostaglandins sensitize nociceptors to pain-provoking mediators such as bradykinin and histamine and, in high concentrations, can directly stimulate sensory nerve endings. TXA 2 is a potent platelet-aggregating agent involved in thrombus formation.

Found predominately in platelets, leukocytes, and the lungs, 5-LOX catalyzes the formation of unstable hydroxyperoxides from AA. These hydroxyperoxides are subsequently converted to peptide leukotrienes, Leukotriene B 4 (LTB 4 ) and 5-hydroxyeicosatetraenoate (5-HETE) are strong chemoattractants stimulating polymorphonuclear leukocyte movement.

LTB 4 also stimulates the production of cytokines in neutrophils, monocytes, and eosinophils and enhances the expression of C3b receptors. Other leukotrienes facilitate the release of histamine and other autacoids from mast cells and stimulate bronchiolar constriction and mucous secretion. In some species, leukotrienes C 4 and D 4 are more potent than histamine in contracting bronchial smooth muscle.

Platelet activating factor (PAF) is also derived from cell membrane phospholipids by the action of PLA 2, PAF, synthesized by mast cells, platelets, neutrophils, and eosinophils, induces platelet aggregation and stimulates platelets to release vasoactive amines and synthesize thromboxanes.

PAF also increases vascular permeability and causes neutrophils to aggregate and degranulate. The role of the free radical gas nitric oxide (NO) in inflammation is well established. NO is an important cell-signaling messenger in a wide range of physiologic and pathophysiologic processes. Small amounts of NO play a role in maintaining resting vascular tone, vasodilation, and antiaggregation of platelets.

In response to certain cytokines (TNF-alpha, IL-1) and other inflammatory mediators, the production of relatively large quantities of NO is stimulated. In larger quantities, NO is a potent vasodilator, facilitates macrophage-induced cytotoxicity, and may contribute to joint destruction in some types of arthritis. Copyright © 2023 Merck & Co., Inc., Rahway, NJ, USA and its affiliates. All rights reserved.

What are the different chemical mediators for pain?

It is necessary to recognize that in spite of the existence of laboratories of high technology and the appearance of surgical innovations, the pain is still at the present time one of the most amazing mysteries which the whole humanity faces. Chemical modulation of pain transmission occurs via several neurotransmitter-receptor systems that have been shown to affect the spinal processing of nociceptive input.

Excitatory neurotransmitters (e.g., substance P), are active in spinal cord and enhance pain transmission.
The inhibitory elements are the opioids, the α 2- adrenergic fibers, γ- aminobutyric acid, and the serotoninergic and adenosinergic receptors.
Endogenous neurotransmitters, like exogenously administered analgesics, work on dorsal horn neurons to inhibit excitatory transmitter release and consequently to decrease pain and perception.

Pain can be the result of the stimulation of the receptors of the pain (nociceptors), which are located in three main body areas: skin, musculoskeletal and visceral structures. Nociception is the neural answer to the application of injurious stimuli. Nociceptive reflex can happen without the perception of the painful stimulate that initiates the reflex.

The perception of the pain is indicated through voluntary actions.
Chemical mediators are important components of the nociceptive reflex and offer a target of pharmacologic modulation.
Pain mediators included: adrenocorticotropic hormone (ACTH), glucocorticoids, vasopressin, oxitocin, catecholamines, brain opiods, angiotensin II, endorphin / encephalin, vasoactive intestinal peptide (VIP), substance P, eicosanoids (e.g., prostaglandins, leukotrienes), tissue kininogens (bradykinin), histamine, serotonin, potassium and proteolytic enzymes.

Bradykinin causes vasodilatation and increase in the vascular permeability, besides to produce hypotension. Additionally, the bradykinin produces pain and causes marginalization of the leukocytes in the blood vessels. Pro-inflammatory effects of substance P include: plasmatic vasodilatation and extravasations; mast cell degranulation, with the consequent histamine release; (iii) leucocytes chemoattractant and proliferation; cytokines release; (v) reactive oxygen intermediates (ROI) production and granular release through polymorphonuclear leukocytes; and increase in production and release of inflammatory mediators.

Histamine is stored in granules of the mast cells. Later to that the mast cells are activated by substances such as IgE, they release histamine, which causes immediate hypersensitivity reactions. This and other effects of histamine are mediated through their interaction with specific receptors, which is in vasodilatation of the post-capillaries venules, besides to bronchi-constriction and increase in the production and flow of bronchial mucus.

Serotonin (5-hidroxytryptamine ) is stored in granules of the dense body of platelets. The 5-HT has vasoconstrictor activity, increases the vascular permeability and promotes fibrosis, these last when increasing synthesis of collagen by the fibroblasts.

The serotonin plays a preponderant role in the descendent inhibiting pathways.
Prostaglandins (PGs), in addition to being mediators of pain, also play a substantial role in the development of pain and oedema.
Prostaglandins per se don’t induce inflammatory signs, but that exacerbate inflammation and pain in the sites of production of mediators of pain, this through activation of specific receptors in the blood vessels and sensitive nerves.

Endogenous opioids (opium-peptins) provides with analgesia when they are released to high concentrations in certain encephalic regions. These include encephalin, dynorphin and endorphin. The inflammatory process implies release of numerous of these chemical mediators, from injured tissues or originating of the own inflammatory cells.

The control of the pain caused by these mediators is frequently widely employee on the control of the inflammatory process. Factors such as emotional state, expectation, attention, blood pressure, stress and drugs can modulate pain, this possibly through the activation of analgesia systems, as the one of opiods.

Pain can be alleviated, or its reduced intensity, through the manipulation of environment or behaviour, in addition to the drug administration. Before the pain is handled with drugs, this it will have initially to be identified and to be classified. All the pain does not require or will respond to drugs.

References 1. Anthony C: Acute pain in the intensive care unit. In: Shoemaker WC, Ayers SM, Genvic A et al (eds). Textbook of Critical Care.3 rd (eds). pp.1486-1498. Philadelphia. WB Saunders.1995.2. Bonica JJ: Biochemistry and modulation of nociception and pain. In: Management of Pain. Lea and Febiger (eds).

Second Edition.1990. pp 96-99.3. Lamont L, Tranquilli WJ & Grimm KG: Physiology of pain. Vet Clin North Am: Small Anim Pract.2000: 30: 703-728.

What chemical produces an inflammatory reaction?

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,

Antigens are substances (usually proteins) on the surface of cells, viruses, fungi, or bacteria. Nonliving substances such as toxins, chemicals, drugs, and foreign particles (such as a splinter) can also be antigens. 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.

This allows your immune system to respond faster and more efficiently the next time you are exposed to the same antigen. In many cases, it will prevent you from getting sick. For example, a person who has had chickenpox or has been immunized against chickenpox is immune from getting chickenpox again. 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.

How do inflammatory mediators cause pain?

Introduction – Clinically, inflammation is characterized by five cardinal signs: rubor (redness), calor (increased heat), tumor (swelling), dolor (pain), and functio laesa (loss of function). Acute inflammation is a protective response involving immune cells, blood vessels, and molecular mediators (inflammatory mediators).

The function of inflammation is to eliminate the initial cause of cell injury and initiate tissue repair. Acute pain, also known as nociceptive pain, is a cardinal feature of inflammation. The majority of known inflammatory mediators cause pain by binding to their receptors on nociceptive primary sensory neurons in the peripheral nervous system (nociceptors) that innervate injured skin, muscle, and joint tissues( 1 – 3 ) ( Fig.1 ).

Once thought to be a passive process, the resolution of acute inflammation is now recognized as a distinct, active process involving specialized pro-resolution mediators (SPM) such as resolvins, protectins, and maresins, derived from omega-3 unsaturated fatty acids( 2, 4 ), as well as other pro-resolution mechanisms( 5 ). Interactions between non-neuronal cells, neurons, and inflammation/neuroinflammation in different pain conditions after injury and insult. Note that non-neuronal cells can modulate pain in different directions by producing either pro- or anti-nociceptive mediators.

In contrast to acute inflammation, chronic inflammation, is often detrimental, leading to a host of diseases, such as periodontitis, atherosclerosis, rheumatoid arthritis, and even cancer( 2 ).
It is unclear if chronic inflammation is also critical for driving chronic pain as acute inflammation is for acute pain.

Pain research in the last several decades has established that neuronal plasticity is a key mechanism for the development and maintenance of chronic pain( 1, 6 ). Peripheral sensitization in nociceptors is essential for the development of chronic pain( 3 ) and transition from acute pain to chronic pain( 7 ).

Central sensitization (i.e.
Enhanced responses of pain circuits in the spinal cord and brain) regulates the chronicity of pain, causes the spread of pain beyond the site of injury, and influences the emotional and affective aspects of pain( 8 ).
Neuroinflammation is a localized inflammation occurring in the PNS and CNS, in response to trauma, neurodegeneration, bacterial/viral infection, autoimmunity, and toxin ( 2, 9 ).

The hallmarkers of neuroinflammation are activation and infiltration of leukocytes, activation of glial cells, and increased production of inflammatory mediators. Neuroinflammation is also associated with changes of vascular cells that facilitate leukocyte infiltration ( 2, 9 ).

Compared to inflammation, neuroinflammation is more persistent in chronic pain conditions, and therefore, plays a more important role in chronic pain maintenance ( 2 ). For example, fibromyalgia, a wide-spread chronic pain syndrome, is associated with small fiber neuropathy and neuroinflammation, although its correlation with systemic inflammation is unclear ( 10 ).

The interactions between inflammation and pain are bidirectional ( Fig.1 ). Nociceptive sensory neurons not only respond to immune signals, but also directly modulate inflammation. For example, nociceptors express receptors for and respond to cytokines and chemokines and also produce these inflammatory mediators ( 11, 12 ).

In a process called neurogenic inflammation, noxious stimulation causes nociceptors to release neuropeptides such as Substance P (SP) and calcitonin gene-related peptide (CGRP), leading to the extravasation of fluid and cells from the blood. Consistently, silencing nociceptors reduces allergic airway inflammation( 13 ).

Nociceptors also serve to dampen and constrain the immune response: ablation of nociceptors abrogated pain during bacterial infection but concurrently worsened inflammation via CGRP( 14 ). Activation of pain circuits also regulates neuroinflammation in the CNS, referred as neurogenic neuroinflammation in chronic pain and neurodegenerative diseases( 9 ).

Numerous non-neuronal cell types influence pain sensation, including immune, glial, epithelial, mesenchymal, cancer, and bacterial cells. In this review, we focus on non-neuronal cells that interact with nociceptors in distinct anatomical compartments in the PNS and CNS (glial cells) under normal and pathological conditions ( Fig.2 ).

Despite the diversity of these cells, the ways in which they modulate pain are surprisingly consistent. In response to an injury or insult, non-neuronal cells release neuromodulatory substances in close proximity to nociceptors, which either promote or dampen pain depending on the specific identities of the mediators involved ( Fig.1 and Fig.2 ). Interactions between distinct parts of a nociceptor with different types of non-neurons cells including keratinocytes, Schwann cells, satellite glial cells, oligodendrocytes, and astrocytes, as well as immune cells (e.g., macrophages and T cells), microglia, cancer cells, and stem cells.

What chemical causes pain in inflammation?

Interleukin-6 is the primary chemical mediator involved in bone inflammation and bone pain.

Is arachidonic acid a chemical mediator?

Abstract – Arachidonic acid is a polyunsaturated fatty acid covalently bound in esterified form in the cell membranes of most body cells. Following irritation or injury, arachidonic acid is released and oxygenated by enzyme systems leading to the formation of an important group of inflammatory mediators, the eicosanoids.

It is now recognised that eicosanoid release is fundamental to the inflammatory process. For example, the prostaglandins and other prostanoids, products of the cyclooxygenase enzyme pathway, have potent inflammatory properties and prostaglandin E2 is readily detectable in equine acute inflammatory exudates.

The administration of nonsteroidal anti-inflammatory drugs results in inhibition of prostaglandin synthesis and this explains the mode of action of agents such as phenylbutazone and flunixin. Lipoxygenase enzymes metabolise arachidonic acid to a group of noncyclised eicosanoids, the leukotrienes, some of which are also important inflammatory mediators.

They are probably of particular importance in leucocyte-mediated aspects of chronic inflammation. Currently available non-steroidal anti-inflammatory drugs, however, do not inhibit lipoxygenase activity. In the light of recent evidence, the inflammatory process is re-examined and the important emerging roles of both cyclo-oxygenase and lipoxygenase derived eicosanoids are explored.

The mode of action of current and future anti-inflammatory drugs offered to the equine clinician can be explained by their interference with arachidonic acid metabolism.

Are macrophages chemical mediators?

Macrophages are also one of the most active secretory cells in the body releasing a vast array of mediators that regulate all aspects of host defense, inflammation and homeostasis including enzymes, complement proteins, cytokines, growth factors, eicosanoids and oxidants.

Is histamine excitatory or inhibitory?

Abstract – Histamine was first identified in the brain about 50 years ago, but only in the last few years have researchers gained an understanding of how it regulates sleep/wake behavior. We provide a translational overview of the histamine system, from basic research to new clinical trials demonstrating the usefulness of drugs that enhance histamine signaling.

The tuberomammillary nucleus is the sole neuronal source of histamine in the brain, and like many of the arousal systems, histamine neurons diffusely innervate the cortex, thalamus, and other wake-promoting brain regions.
Histamine has generally excitatory effects on target neurons, but paradoxically, histamine neurons may also release the inhibitory neurotransmitter GABA.

New research demonstrates that activity in histamine neurons is essential for normal wakefulness, especially at specific circadian phases, and reducing activity in these neurons can produce sedation. The number of histamine neurons is increased in narcolepsy, but whether this affects brain levels of histamine is controversial.

What are the major chemical mediators?

What are the 5 symptoms of local inflammation?

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,

Furthermore, inflammation is considered the cornerstone of pathology in that the changes observed are indicative of injury and disease.
The classical description of inflammation accounts for the visual changes seen.
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).

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.

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.

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.

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.

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.

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.
This research led to the development of indomethacin, the fenamates, ibuprofen and many others.
However, while all these drugs had clinical utility they also eroded 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,

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.

Many of these adverse effects can be avoided by giving glucocorticoids topically. 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. However, applying this approach to the treatment of rheumatoid arthritis necessitates the use of intra-articular injection.

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.

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.

Is serotonin a chemical mediator?

C5a is a potent chemotactic factor for neutrophils and mononuclear phagocytes.
The kinins are also important inflammatory mediators.
The most important kinin is bradykinin, which increases vascular permeability and vasodilation and, importantly, activates phospholipase A 2 (PLA 2 ) to liberate arachidonic acid (AA).

Its release is stimulated by the complement components C3a and C5a and by lysosomal proteins released from neutrophils.
Histamine activity is mediated through the activation of one of four specific histamine receptors, designated H 1, H 2, H 3, or H 4, in target cells.
Most histamine-induced vascular effects are mediated by H 1 receptors.

Serotonin (5-hydroxytryptamine) is a vasoactive mediator similar to histamine found in mast cells and platelets in the gastrointestinal tract and the CNS.
Serotonin also increases vascular permeability, dilates capillaries, and causes contraction of nonvascular smooth muscle.
In some species, including rodents and domestic ruminants, serotonin may be the predominant vasoactive amine.

These polypeptides modulate the activity and function of other cells to coordinate and control the inflammatory response.
Two of the more important cytokines, interleukin-1 (IL-1) and TNF-alpha, mobilize and activate leukocytes, enhance proliferation of B and T cells and natural killer cell cytotoxicity, and are involved in the biologic response to endotoxins.

By increasing intracellular Ca 2+ concentrations in leukocytes, cytokines are also important in the induction of PLA 2, Colony-stimulating factors (GM-CSF, G-CSF, and M-CSF) are cytokines that promote expansion of neutrophil, eosinophil, and macrophage colonies in bone marrow. In chronic inflammation, cytokines IL-1, IL-6, and TNF-alpha contribute to the activation of fibroblasts and osteoblasts and to the release of enzymes such as collagenase and stromelysin that can cause cartilage and bone resorption.

These compounds include the eicosanoids such as prostaglandins, prostacyclin, leukotrienes, and thromboxane A and the modified phospholipids such as platelet activating factor (PAF). Eicosanoids are synthesized from 20-carbon polyunsaturated fatty acids by many cells, including activated leukocytes, mast cells, and platelets and are therefore widely distributed.

Activated PLA 2 directly hydrolyzes AA, which is rapidly metabolized via one of two enzyme pathways—the cyclooxygenase (COX) pathway leading to the formation of prostaglandin and thromboxanes, or the 5-lipoxygenase (5-LOX) pathway that produces the leukotrienes. Cyclooxygenase catalyzes the oxygenation of AA to form the cyclic endoperoxide PGG 2, which is converted to the closely related PGH 2,

Other prostaglandins, including PGF2alpha and thromboxane, cause smooth muscle contraction and vasoconstriction.
Prostaglandins sensitize nociceptors to pain-provoking mediators such as bradykinin and histamine and, in high concentrations, can directly stimulate sensory nerve endings.
TXA 2 is a potent platelet-aggregating agent involved in thrombus formation.

LTB 4 also stimulates the production of cytokines in neutrophils, monocytes, and eosinophils and enhances the expression of C3b receptors. Other leukotrienes facilitate the release of histamine and other autacoids from mast cells and stimulate bronchiolar constriction and mucous secretion. In some species, leukotrienes C 4 and D 4 are more potent than histamine in contracting bronchial smooth muscle.

What are the different chemical mediators for pain?

Excitatory neurotransmitters (e.g., substance P), are active in spinal cord and enhance pain transmission.
The inhibitory elements are the opioids, the α 2- adrenergic fibers, γ- aminobutyric acid, and the serotoninergic and adenosinergic receptors.
Endogenous neurotransmitters, like exogenously administered analgesics, work on dorsal horn neurons to inhibit excitatory transmitter release and consequently to decrease pain and perception.

The perception of the pain is indicated through voluntary actions. Chemical mediators are important components of the nociceptive reflex and offer a target of pharmacologic modulation. Pain mediators included: adrenocorticotropic hormone (ACTH), glucocorticoids, vasopressin, oxitocin, catecholamines, brain opiods, angiotensin II, endorphin / encephalin, vasoactive intestinal peptide (VIP), substance P, eicosanoids (e.g., prostaglandins, leukotrienes), tissue kininogens (bradykinin), histamine, serotonin, potassium and proteolytic enzymes.

Histamine is stored in granules of the mast cells.
Later to that the mast cells are activated by substances such as IgE, they release histamine, which causes immediate hypersensitivity reactions.
This and other effects of histamine are mediated through their interaction with specific receptors, which is in vasodilatation of the post-capillaries venules, besides to bronchi-constriction and increase in the production and flow of bronchial mucus.

The serotonin plays a preponderant role in the descendent inhibiting pathways. Prostaglandins (PGs), in addition to being mediators of pain, also play a substantial role in the development of pain and oedema. Prostaglandins per se don’t induce inflammatory signs, but that exacerbate inflammation and pain in the sites of production of mediators of pain, this through activation of specific receptors in the blood vessels and sensitive nerves.

The control of the pain caused by these mediators is frequently widely employee on the control of the inflammatory process.
Factors such as emotional state, expectation, attention, blood pressure, stress and drugs can modulate pain, this possibly through the activation of analgesia systems, as the one of opiods.

References 1.
Anthony C: Acute pain in the intensive care unit.
In: Shoemaker WC, Ayers SM, Genvic A et al (eds).
Textbook of Critical Care.3 rd (eds).
Pp.1486-1498.
Philadelphia.
WB Saunders.1995.2.
Bonica JJ: Biochemistry and modulation of nociception and pain.
In: Management of Pain.
Lea and Febiger (eds).

Second Edition.1990. pp 96-99.3. Lamont L, Tranquilli WJ & Grimm KG: Physiology of pain. Vet Clin North Am: Small Anim Pract.2000: 30: 703-728.

Chukwudi Eze