Gastric Secretion and Its Regulation

April 2, 2016 Gastroenterology, Physiology and Pathophysiology No comments , , , , , , , , , ,

Regulation Mechanism of Gastrirc Secretion

Short and Long Reflexes

Neural input provides an important mechanism for regulation of gastric secretion. Reflexes contribute to both the stimulation and inhibition (e.g., CGRP) of secretion. For example, distension of the stomach wall, sensed by stretch receptors, activates reflexes that stimulate acid secretion at the level of the parietal cell. These reflexes may be so-called short reflexes, which involve neural transmission contained entirely within the enteric nervous system. In addition, long reflexes also contribute to the control of secretion. These involve the activation of primary afferents that travel through the vagus nerve, which in turn are interpreted in the dorsal vagal complex and trigger vagal outflow via efferent nerves that travel back to the stomach and activate parietal cells or other components of the secretory machinery. These long reflexes are aslo called vagovagal reflexes. The relative contribution of short and long reflexes to the control of secretion is unknown. However, it is clear that selective gastric vagotomy eliminates some, although not all, of the gastric secretory response to distension as well as a portion of related gastric motor responses.

Acetylcholine is an important mediator of both short and long reflexes in the stomach. It participates in the stimulation of parietal, cheif, and ECL cells; the supression of D cells; and the synapses between nerves within the enteric nervous system. In addition, a second imporant gastric neurotransmitter is gastrin releasing peptide, or GRP. This neuropeptide is the mammalian homologue of one known as bombesin originally isolated from frog skin. GRP is released by enteric nerves in the vicinity of gastrin-containing G cells in the gastric antrum.

  • Short reflexes, ENS (ACh)
  • Long reflexes/vagovagal reflexes, ANS (ACh)
  • GRP
  • CGRP

Humoral Control

The gastric secretory response is also regulated by soluble factors that originate from endocrine and other regulatory cell types, such as ECL cells. The primary endocrine regulator of gastric secretion is gastrin, which actually consists of a family of peptides. Gastrin travels through the bloodstream from its site of release in the antral mucosa to stimulate parietal and ECL cells via their CCK2 receptors.

PS: CCK2 receptors are expressed on the parietal and ECL cells.

Gastric secretion is also modified by paracrine mediators. Histamine is released from ECL cells under the combined influence of gastrin and ACh, and diffuses to neighboring parietal cells to activate acid secretion via histamine H2 receptors. At one time histamine was thought to be the final common mediator of acid secretion, based in part on the clinical observation that histamine H2 receptor antagonists can profoundly inhibit acid secretion. However, it is now known that parietal cells express receptors for not only histamine, but also ACh (muscarinic m3) and gastrin (CCK2). Because histamine H2 receptors are linked predominantly to signaling pathways that involve cAMP, while ACh and gastrin signal through calcium, when the parietal cell is acted upon simultaneously by all three stimuli, a potentiated, or greater than additive, effect on acid secretion results. The physiological implication of this potentiation, or synergism, is that a greater level of acid secretion can be produced with relatively small increases in each of the three stimuli. The pharmacological significance is that simply interfering with the action of any one of them can significantly inhibit acid secretion.

Acid secretion is also subject to negative regulation by specific mediators. Specifically, somatostatin is released from D cells in response to an axon reflex that release CGRP (calcitonin gene-related peptide) in the antral mucosa when luminal pH falls below 3, and inhibits the release of gastrin from G cells. Elsewhere in the stomach, somatostatin can also exert inhibitory influences on ECL, parietal, and chief cells. The SSTR2 somatostatin receptor is responsible for the inhibitory effects of the peptide in the stomach. In fact, there is data to support the idea that gastirc secretion under resting conditions is tonically suppressed by somatostatin. When stimulated responses occur, they are due not only to the active stimulatory mechanisms disscussed above, but also specific suppression of the inhibitory effects of somatostatin, involving the actions of both ACh (via m2 and m4 receptors) and histamine (via H3 receptors) on D cells.

  • Gastrin
  • Histamine
  • Somatostatin (negative regulation)

Luminal Regulators

Specific luminal constituents also modulate gastric secretion indirectly. The example of pH is described earlier, but acid output, at least, is also increased by components of the meal. Short peptides and amino acids, derived from dietary protein secondary to the action of pepsin released from chief cells, are capable of activating gastrin release from G cells. Aromatic amino acids are the most potent, and "receptors" for these are assumed to reside on the apical membrane of the open G-type endocrine cells, although their structure remains to be defined.

Gastric acid secretion is also activated by alcoholic beverages, coffee, and dietary calcium. The effects of alcoholic beverages may not be due to ethanol itself, but rather the amino acids present in the veverage, particularly in beer and wine. Likewise, the effect of coffee does not appear to be attributable to caffeine, since decaffeinated coffee also increases secretion.

  • Food (bufferring/increasing pH)
  • Food (short peptides and amino acids, alcoholic beverages, coffee, dietary calcium)

Summar of Regulators of Gastric Secretion

Product Source Function
Histamine ECL cells amplify acid secretion
    suppress somatostatin secretion
Gastrin G cells amplify acid secretion
    amplify histamine secretion
GRP Nerves stimuate the secretion of gastrin
CGRP Nerves stimulate the secreton of somatostatin
Ach Nerves amplify acid secretion
    amplify pepsinogen secretion
    amplify histamine secretion
    suppress somatostatin secretion
Somatostatin D cells suppress gastrin secretion
    suppress histamine secretion
    suppress acid secretion
    suppress pepsinogen secretion

Regulation of Gastric Secretion

Regulation of Scretion in the Interdigestive Phase

Between meals, the stomach secretes acid and other secretory products at a low level, perhaps to aid in maintaining the sterility of the stomach. However, because no food is present, and thus no buffering capacity of the gastric content, the low volume of secretions produced nevertheless have a low pH – usually around 3.0. Basal acid output in the healthy human is in the range of 0-11 mEq/h, which can be contrasted with the maximal rates that can be produced by ingestion of a meal, or intravenous administration of gastrin, of 10-63 mEq/h. The basal secretion rate is believed to reflect the combined influences of histamine and ACh, released from ECL cells and nerve endings, respectively, tempered by the influence of somatostatin from fundic D cells. Gastrin secretion during the interdigestive period, on the other hand, is minimal. This is because gastrin release is suppressed by a luminal pH of 3 or below, via the release of somatostatin from antral D cells.

Regulation of Postprandial Secretion

In conjunction with a meal, gastric acid secretion can be considered to occur in three phases – cephalic, gastric, and intestinal. The major portion of secretion occurs during the gastric phase, when the meal is actually present in the stomach. Secretion of other gastric products usually parallels that of the acid.

Cephalic Phase

Even before the meal is ingested, the stomach is readied to receive it by the so-called cephalic phase of secretion. In fact, during the cephalic phase, the functions of several gastrointestinal systems in addition to the stomach begin to be regulated, including the pancreas and gallbladder. Higher brain centers respond to the sight, smell, taste and even thought of food, and relay information to the dorsal vagal complex. In turn, vagal outflow initiates both secretory and motor behavior in the stomach and more distal segments. Gastric secretion occuring during the cephalic phase readies the stomach to receive the meal. Vagal outflow activates enteric nerves that in turn release GRP and ACh. Release of GRP in the vicinity of antral G cells releases gastrin that travels through the bloodstream to activate parietal and chief cells in the endocrine fashion. ACh also suppresss ongoing somatostatin release.

Gastric Phase

The gastric phase of secretion is quantitatively the most important. In addition to vagal influences continuing from the cephalic phase, secretion is now amplified further by mechanical and chemical stimuli that arise from the presence of the meal in the lumen. These include the luminal signals discussed earlier, and signals arising from stretch receptors embedded in the wall of the stomach. Thus, as the stomach distends to accommodate the volume of the meal, these receptors initiate both short and long reflexes to further enhance secretory responses either directly, via the release of ACh in the vicinity of parietal cells, or indirectly, via the release of ACh that activate ECL cells, or GRP that activates G cells to release gastrin. These vago-vagal reflexes also transmit information downstream to ready more distal segments of the intestine to receive the meal. The gastric phase of secretion is also accompanied by a marked increase in gastric blood flow, which supplies the metabolic requirements of the actively secreting cell types.

Due to the combined influence of neurocrine and endocrine signals, further amplified by histamine release from ECL cells, secretory cells of the stomach are highly active during the gastric phase. Moreover, pepsinogen released by chief cells is rapidly cleaved to pepsin in an autocatalytic reaction that occurs optimally at pH 2, and this pepsin then acts on ingested protein to release short peptides and amino acids that further enhance gastrin release. Moreover, many dietary substances, including proteins, are highly effective buffers. Thus, while acid secretory rates remain high, the effective pH in the bulk of the lumen may rise to pH 5. This ensures that the rate of acid secretion during the gastric phase is not attenuated by an inhibition of gastrin release that would otherwise be mediated by somatostatin (when pH <=3).

Intestinal Phase

As the meal moves out of the stomach into the duodenum, the buffering capacity of the lumen is reduced and the pH begins to fall. At a threshold of around pH 3, CGRP triggers somatostatin release from D cells in the gastric antrum, which acts on G cells to suppress gastrin release. Somatostatin released from D cells in the oxyntic mucosa, or from nerve endings, likely also acts directly to inhibit secretory function. This acid-sensing response is a neural pathway that involves the activation of chemoreceptors sensitive to pH, which in turn leads to the release of CGRP via an axon reflex. Other signals also limit the extent of gastric secretion when the meal has moved into the small intestine. For example, the presence of fat in the small intestine is associated with a reduction in gastric secretion. This feedback response is believed to involve several endocrine and paracrine factors, including GIP and CCK, the latter of which binds to CCK1 receptors on D cells.

(The End)

Arteriolar Tone and Its Regulation (Local Mechanisms)

July 17, 2015 Cardiology, Physiology and Pathophysiology No comments , , , , , , , , , , , , , , , , ,


I.Arteriolar Tone

A.Basal tone


C.Adrenal Glands


1.Metabolic substances

2.Endothelial cells secretion

3.Other local chemical influences

4.Transmural pressure (myogenic response)

II.Venous Tone

A.Basal tone (little)


C.Adrenal glands

D.Internal pressure (recall deltaV/deltaP = C)

E.External compression (muscle pump)

Because the body's needs are continually changing, the cardiovascular system must continually make adjustments in the diameter of its vessels. The purposes of these vascular change are 1.to efficiently distribute the cardiac output among tissues with different current needs (the job of arterioles) and 2.to regulate the distribute of blood volume and cardiac filling (the job of veins). So besides central regulatory mechanisms for vascular system (CNS, autonomic nerves system) and hormonal regulatory mechanisms (RAAS/angII and vasopressin, natriuretic hormone, insulin resistance and hyperinsulinemia, circulating catecholamines), there are another vascular regulatory mechanism – peripheral regulatory mechanisms/local mechanisms.

Total peripheral resistance (TPR) is determined by resistances of each primary organs and tissues, whereas resistance of an single organ or tissue region is primarily determined by resistances of arterioles that distribute within this organ or tissue. Therefore, TPR is determined primarily by resistance of arterioles. According to the famous Hagen–Poiseuille equation, resistance to flow is inversely and directly related to the radius of the vessel.

(Note: Q = ΔP/R, and R is resistance of the vessel)

Because resistances of arterioles are so important for TPR and the resultant blood flow (Q), we need to study the characteristics of arteriolar resistance carefully. Vascular tone is a term commonly used to characterize the general contractile state (so the radius of the vessel) or a vascular region. The "vascular tone" of a region can be taken as an indication of the "level of activation" of the individual smooth muscle cells in that region. Because the blood flow through any organ is determined largely by its vascular resistance, which dependent primarily on the diameter of its arterioles, thus an organ's flow is controlled by factors that influence the arteriolar smooth muscle tone.

Arterioles remain in a state of partial constriction even all external influences on them are removed; hence, they are said to have a degree of basal tone. The understanding of the mechanism is incomplete, but basal arteriolar tone may be a reflection of the fact that smooth muscle cells inherently and actively resist being stretched as they continually are in pressurized arterioles. Another hypothesis is that the basal tone of arterioles is the result of a tonic production of local vasoconstrictor substances by the endothelial cells that line their inner surface. Nevertheless, the arterioles have basal tone, and several factors externally influence it, including local influences, neural influences, and hormonal influences.


The capacity of tissues to regulate their own blood flow is referred to as auto regulation. Most vascular beds have an intrinsic capacity to compensate for moderate changes in perfusion pressure by change in vascular resistance, so that blood flow remains relatively constant. The ability of vascular autoregulation is probably due in part to the intrinsic contractile response of smooth muscle to stretch (myogenic theory of autoregulation). That is, as the perfusion pressure rises, the blood vessels are distended and the vascular smooth muscle fivers that surround the vessels contract, which increases the vascular resistance so that the blood flow remains constant (Q = ΔP/R). At the last section of this thread you can find more detail information for the mechanisms and rationales about vascular autoregulation.

General Mechanisms for Activation of the Vascular Smooth Muscle

The task of the vascular smooth muscle is unique, because to maintain a certain vessel diameter in the face of the continual distending pressure of the blood within it, the vascular smooth muscle must be able to sustain active tension for prolonged periods. Compared with other muscle types, smooth muscle cells have these different characteristics, including:

1.Contract and relax much more slowly;

2.Can change their contractile activity as a result of either action potentials or changes in resting membrane potential;

3.Can change their contractile activity in the absence of any change in membrane potential;

4.Can maintain tension for prolonged periods at low energy cost;


5.Can be activated by stretch.

Local Influences on Basal Tone

Local factors influencing arteriolar basal tone (and the diameter of arterioles) include metabolic influences, endothelial cells, other chemical influences, and transmural pressure.

Metabolic Substances. The arterioles that control flow through a given organ lie within the organ tissue itself. Thus, arterioles and the smooth muscle in their walls are exposed to the chemical composition of the interstitial fluid of the organ they serve. The interstitial concentrations of many substances reflect the balance between the metabolic activity of the tissue and its blood supply. Exposure to low oxygen, and metabolic substances such as high H+, high K+, high CO2, high osmolarity, and adenosine, cause reduced arteriolar tone and vasodilation. By contrary, exposure to high oxygen and low metabolic substances induce increased arteriolar tone and vasoconstriction. When metabolic activity is over the blood supply, oxygen pressure in that tissue gets lower and the metabolic wastes accumulate in the tissue, which cause vasodilation of arterioles. As a result of arteriolar vasodilation, the blood supply to that tissue is improved and oxygen pressure gets back to normal or even higher, whereas increased amount of metabolic wastes are washed away by the improved blood flow therefore the accumulation of metabolic wastes is resolved. Finally, the basal tone gets back to normal.

Endothelial cells cover the entire inner surface of the cardiovascular system. A large number of studies have shown that the blood vessels respond very differently to certain vascular influences when their endothelial lining is missing. In the case of the vasodilator effect of infusing acetylcholine through intact vessels, the vasodilator influence produced by endothelial cells has been identified as nitric oxide. Nitric oxide is produced within endothelial cells from the amino acid, L-arginine, by the action of an enzyme, nitric oxide synthase. Nitric oxide synthase is activated by a rise in the intracellular level of the Ca2+. And nitric oxide is a small lipid-soluble molecule that, once formed, easily diffuses into adjacent smooth muscle cells where it causes relaxation by stimulating cGMP production.

Acetylcholine and several other agents such as bradykinin, vasoactive intestinal peptide, and substance P stimulate endothelial cell nitric oxide production because their receipts on endothelial cells are linked to receptor-operated Ca2+ channels. Probably more importantly from a physiological standpoint, flow-related shear stresses on endothelial cells stimulate their nitric oxide production presumably because stretch-sensitive channels for Ca2+ are activated. Such flow-related endothelial cell nitric oxide production may explain why, for example, exercise and increased blood flow through muscles of the lower leg can cause dilation of the blood-supplying femoral artery at points far upstream of the exercising muscle itself.

One general unresolved issue with the concept that arteriolar tone is regulated by factors produced by arteriolar endothelial cells is how these cells could know what the metabolic needs of the downstream tissue are. This is because the endothelial cells lining arterioles are exposed to arterial blood whose composition is constant regardless of flow rate or what is happening downstream. One hypothesis is that there exists some sort of communication system between vascular endothelial cells. That way, endothelial cells in capillaries or venules could telegraph upstream information about whether the blood flow is indeed adequate.

Other local chemical influences. Many specific locally-produced and locally-reacting chemical substances have been identified that have vascular effects and therefore could be important in local vascular regulation in certain instances. In most cases, however, definite information about the relative importance of these substances in cardiovascular regulation is lacking. Prostaglandins are a group of several chemically related products of the cyclooxyrgenase pathways of arachidonic acid metabolism, which have vasoactive effects. Certain prostaglandins are potent vasodilators, while some are potent vasoconstrictors. However, despite the vasoactive potency of the prostaglandin and the fact that most tissues are capable of synthesizing prostaglandins, it has not been demonstrated convincingly that prostaglandins play a crucial role in the normal vascular control.

Histamine is synthesized and stored in high concentrations in secretory granules of tissue mast cells and circulating basophils. When released, histamine produces arteriolar vasodilation (via the cAMP pathway) and increases vascular permeability (by causing separations in the junctions between the endothelial cells that line the vascular system), which leads to edema formation and local tissue swelling. Other effects that histamine plays include stimulation of sensory nerve endings to produce itching and pain sensation.

Bradykinin is a small polypeptide that has approximately ten times the vasodilator potency of histamine on a molar basis. It also acts to increase capillary permeability by opening the junctions between endothelial cells. Bradykinin is formed from certain plasma globulin substances by the action of an enzyme, kvllikrein, and is subsequently rapidly degraded into inactive fragments by various tissue kinases.

Transmural pressure. The effect of transmural pressure on arteriolar diameter is more complex because arterioles respond both passively and actively to changes in transmural pressure. For example, a sudden increases in the internal pressure within an arteriole produces: 1.first an initial slight passive mechanical distention, and 2.then an active constriction that, within seconds, may completely reverse the initial distention. A sudden decrease in transmural pressure elicits essentially the opposite response, that is, an immediate passive decrease in diameter followed shortly by a decrease in active tone, which returns the arteriolar diameter to near that which existed before the pressure change. The active phase of such behavior is referred to as a myogenic response, because it seems to originate within the smooth muscle itself. The mechanism of the myogenic response is not known for certain, but stretch-sensitive ion channels on arteriolar vascular smooth muscle cells are likely candidates for involvement.

Examples of Local Regulation

Active Hyperemia – In organs with a highly variable metabolic rate, such as skeletal and cardiac muscles, the blood flow closely follows the tissue's metabolic rate. For example, skeletal muscle blood flow increases within seconds of the onset of muscle exercise and returns to control values shortly after exercise ceases. This phenomenon, which is illustrated in Figure 7-3A, is known as exercise or active hyperemia. Active hyperemia could be explained by mechanisms related to local metabolic theory and to local flow-related shear stresses theory.Screen Shot 2015-07-17 at 8.11.32 PM

Reactive Hyperemia – In this case, the higher-than-normal blood flow occurs transiently after the removal of any restriction that has caused a period of lower-than-normal blood flow and is sometimes referred to as post occlusion hyperemia. The phenomenon is illustrated in Figure 7-3B. For example, flow through an extremity is higher than normal for a period after a tourniquet is removed from the extremity. Both local metabolic and myogenic mechanisms may be involved in producing reactive hyperemia.

Autoregulation talks about the arterioles' reaction to the changes of the perfusion pressure. Except when displaying active and reactive hyperemia, nearly all organs tend to keep their blood flow constant despite variations in arterial pressure – that is, they autoregulate their blood flow. For example, an abrupt increase in arterial pressure is normally accompanied by an initial abrupt increase in organ blood flow that then gradually returns toward normal despite the sustained elevation in arterial pressure. The later autoregulation that returns the flow toward the normal level is caused by a gradual increase in active arteriolar tone and resistance to blood flow. Ultimately, a new steady state is reached with only slightly elevated blood flow because the increased driving pressure is counteracted by a higher-than-normal vascular resistance. The mechanisms for autoregulation are believed to be both local metabolic feedback theory and myogenic theory. Also, tissue pressure hypothesis of blood flow auto regulation for which it is assumed that an abrupt increase in arterial pressure causes transcapillary fluid filtration and thus leads to a gradual increase in interstitial fluid volume and pressure. Presumably the increase in extravascular pressure would cause a decrease in vessel diameter by simple compression. This mechanism might be especially important in organs such as the kidney and brain whose volumes are constrained by external structures.


Inflammation Mediators

March 9, 2015 Infectious Diseases, Pharmacology, Pharmacotherapy, Physiology and Pathophysiology No comments , , , , , , ,

The mediators of inflammation are the substances that initiate and regulate inflammatory reactions. The most important inflammation mediators include vasoactive amineslipid products (prostaglandins and leukotrienes), cytokines (including chemokines), and products of complement activation. These mediators induce various components of the inflammatory response typically by distinct mechanisms, which is why inhibiting each has been therapeutically beneficial. However, there is also some overlap (redundancy) in the actions of the mediators.

The inflammation mediators have some common characteristics, like

  • Mediators are either secreted by cells or generated from plasma proteins. Cell-derived mediators are normally sequestered in intracellular granules and can be rapidly secreted by granule exocytosis (e.g., histamine in mast cell granules) or are synthesised de novo (e.g., prostaglandins and leukotrienes, cytokines) in response to a stimulus. The major cell types that produce mediators of acute inflammation are the sentinels that detect invaders and damage in tissues, that is, macrophages, dendritic cells, and mast cells, but platelets, neutrophils, endothelial cells, and most epithelia can also be induced to elaborate some of the mediators. Plasma derived mediators (e.g., complement proteins) are produced mainly in the liver and are present in the circulation as inactive precursors that must be activated. When activated a series of proteolytic and protein-protein interactions are initiated that ultimately to acquire their biologic properties.
  • Ative mediators are produced only in response to various stimuli. These stimuli include microbial products and substances released from necrotic cells. Some of the stimuli trigger well-defined receptors and signalling pathways.
  • Most of the mediators are short-lived. They quickly decay, or are inactivated by enzymes, or they are otherwise scavenged or inhibited. There is thus a system of checks and balances that regulates mediator actions.
  • One mediator can stimulate the release of other mediators. The secondary mediators may have the same actions as the initial mediators but may also have different and even opposing activities. Such cascades provide mechanisms for amplifying or, in certain instances, counteracting the initial action off a mediator.

Vasoactive Amines: Histamine and Serotonin

The two major vasoactive amines, so named because they have important actions on blood vessels, are histamine and serotonin. They are stored as preformed molecules in cells and are therefore among the first mediators to be released during inflammation. The richest sources off histamine are the mast cells that are normally present in the connective tissue adjacent to blood vessels. It is also found in blood basophils and platelets. Histamine is stored in mast cell granules and is released by mast cell degranulation in response to a variety of stimuli, including 1.physical injury, such as trauma, cold, or heat, by unknown mechanisms;2.binding of antibodies to mast cells, which underlies immediate hypersensitivity (allergic) reactions; and 3.products of complement called anaphylatoxins (C3a and C5a). Antibodies and complement products bind to specific receptors on mast cells and trigger signalling pathways that induce rapid degranulation. In addition, leukocytes are thought to secrete some histamine-releasing proteins but these have not been characterised. Neuropeptides (e.g., substance P) and cytokines (IL-1, IL-8) may also trigger release of histamine.

Histamine causes dilation of arterioles and increases the permeability of venules. Histamine is considered to be the principle mediator of the immediate transient phase of increased vascular permeability, producing interendothelial gaps in venules. Its vasoactive effects are mediated mainly via binding to receptors, called H1 receptors, on microvascular endothelial cells. Histamine also causes contraction of some smooth muscles.

Serotonin is a preformed vasoactive mediator present in platelets and certain neuroendocrine cells, such as in the gastrointestinal tract, and in mast cells in rodents but not humans. Its primary function is as a neurotransmitter in the gastrointestinal tract. It is also a vasoconstrictor, but the importance of this action in inflammation is unclear.

Arachidonic Acid Metabolites

The lipid mediators prostaglandins and leukotrienes are produced from arachidonic acid (AA) present in membrane phospholipids, and stimulate vascular and cellular reactions in acute inflammation. AA does not occur free in the cell but is normally esterified in membrane phospholipids. Mechanical, chemical, and physical stimuli or other mediators (e.g., C5a) release AA from membrane phospholipids through the action of cellular phospholipases, mainly phospholipase A2. The biochemical signals involved in the activation of phospholipase A2 include an increase in cytoplasmic Ca2+ and activation of various kinases in response to external stimuli. AA-derived mediators, also called eicosanoids are synthesised by two major classes of enzymes: cyclooxygenases (for prostaglandins) and lipoxygenases (for leukotrienes). Eicosanoids bind to G protein-coupled receptors on many cell types and can mediate virtually every step of inflammation, including vasodilation (PGI2, PGE1, PGE2 PGD2), vasoconstriction (TxA2/Thromboxane A2, leukotrienes C4/D4/E4), increased vascular permeability (Leukotrienes C4/D4/E4), Chemotaxis, leukocyte adhesion (Leukotrienes B4/HETE or Hydroxyeicosatetraenoic acid).

  • Prostaglandins

Prostaglandins (PGs) are produced by mast cells, macrophages, endothelial cells, and many other cell types, and are involved in the vascular and systemic reactions of inflammation. They are generated by the actions of two cyclooxgenases, called COX-1 and COX-2. COX-1 is produced in response to inflammatory stimuli and is also constitutively expressed in most tissues, where it may serve a homeostatic function (e.g., fluid and electrolyte balance in the kidneys, cytoprotection in the gastrointestinal tract). In contrast, COX-2 is induced by inflammatory stimuli and thus generates the prostaglandins that are involved in inflammatory reactions, but it is low or absent in most normal tissues. Prostaglandins include many subtype PGs, such as TxA2, PGI2, PGD2, PGE2, PGF2a etc. These subtype prostaglandins are derived by the action of different enzymes on an intermediate in the pathways, respectively.

TxA2, a potent platelet-aggregating agent and vasoconstrictor is derived by the enzyme thromboxane synthase which locates in the platelets. Prostacyclin synthase in vascular endothelium catalyze the production of PGI2 and PGI2 has functions as vasodilator,  a potent inhibitor of platelet aggregation, and markedly potentiates the permeability-increasing and chemotactic effects of other mediators. PS: a thromboxane-prostacyclin imbalance has been implicated as an early event in thrombus formation in coronary and cerebral blood vessels. PGD2 is the major prostaglandin made by mast cells; along with PGE2 (which is more widely distributed), it causes vasodilation and increases the permeability of post capillary venules, thus potentiating edema formation. Also it has a function of chemoattractant for neutrophils. PGF2a stimulates the contraction of uterine and bronchial smooth muscle and small arterioles.

In addition to their local effects, the prostaglandins are involved in the pathogenesis of pain and fever in inflammation. PGE2 is hyperalgesic and makes the skin hypersensitive painful stimuli, such as intradermal injection of suboptimal concentrations of histamine and bradykinin. It is also involved in cytokine-induced fever during infections.

  • Leukotrienes

Leukotrienes are produced by leukocytes and mast cells by the action of lipoxygenase and are involved in vascular and smooth muscle reactions and leukocyte recruitment. There are three different lipoxygenases, 5-lipoxygenase being the predominant one in neutrophils. This enzyme converts AA (arachidonic acid) to 5-hydroxyeicosatetraenoic acid, which is chemotactic for neutrophils, and is the precursor of the leukotrienes. Among leukotrienes, LTB4 is a potent chemotactic agent and activator of neutrophils, causing aggregation and adhesion of the cells to ventral endothelium, generation of ROS (reactive oxygen species), and release of lysosomal enzymes. The LTC4, LTD4, and LTE4 cause intense vasoconstriction, bronchospasm (important in asthma), and increased permeability of venules. Leukotrienes are more potent than is histamine in incresing vascular permeability and causing bronchospasm.

  • Lipoxins

Lipoxins are also generated from AA by the lipoxygenase pathway, but unlike prostaglandins and leukotrienes, the lipoxins suppress inflammation by inhibiting the recruitment of leukocytes. They inhibit neutrophil chemotaxis and adhesion to endothelium. They are also unusual in that two cell populations are required for the transcellular biosynthesis of these mediators. Leukocytes, particularly neutrophils, produce intermediates in lipoxin synthesis, and these are converted to lipoxins by platelets interacting with the leukocytes.

Cytokines and Chemokines

  • Cytokines

Cytokines are proteins produced by many cell types (principally activated lymphocytes, macrophages, and dendritic cells, but also endothelial, epithelial, and connective tissue cells) that mediate and regulate immune and inflammatory reactions. They include TNF (tutor necrosis factor) and Interleukin-I (IL-1). These cytokines are produced mainly by activated macrophages and dendritic cells; TNF is also produced by T lymphocytes and mast cells, and IL-1 is produced by some epithelial cells as well. The most important roles of these cytokines in inflammation are the following:

Screen Shot 2015-11-11 at 7.40.44 PM1.Endothelial activation. Both TNF and IL-1 act on endothelium to induce a spectrum of changes referred to as endothelial activation. These changes include increased expression of endothelial adhesion molecules, mostly E- and P-selectins and ligands for leukocyte integrins; increased production of various mediators, including other cytokines and cheekiness, growth factors, and eicosanoids; and increased procoagulant activity of the endothelium.

2.Activation of leukocytes and other cells. TNF augments responses of neutrophils to other stimuli such as bacterial endotoxin and stimulates the microbicidal activity of macrophages, in part by inducing production of NO. IL-1 activates fibroblasts to synthesize collagen and stimulates proliferation of synovial and other mesenchymal cells. IL-1 also stimulates TH17 responses, which in turn induce acute inflammation.

3.Systemic acute-phase response. IL-1 and TNF induce the systemic acute-phase responses associated with infection or injury, including fever. They are also implicated in the syndrome of sepsis, resulting from disseminated bacterial infection. TNF regulates energy balance by promoting lipid and protein mobilisation and by suppressing appetite. Therefore, sustained production of TNF contributes to cachexia, a pathologic state characterised by weight loss and anorexia that accompanies some chronic infections and neoplastic disease.

  • Chemokines

Cheekiness are a family of small (8 to 10 kD) proteins that act primarily as chemoattractants for specific types of leukocytes. Inflammatory chemokines stimulate leukocyte attachment to endothelium by acting on leukocytes to increase the affinity of integrins, and they stimulate migration (chemotaxis) of leukocytes in tissue to the site of infection or tissue damage. Also, some chemokines are produced constitutively in tissues and are sometimes called homeostatic chemokines. These organize various cell types in different anatomic regions of the tissues.

Complement System

The complement system is a collection of soluble proteins and membrane receptors that function mainly in host defines against microbes and in pathologic inflammatory reactions. This system of complement functions in both innate and adaptive immunity for defines against microbial pathogens. In the process of complement activation, several cleavage products of complement proteins are elaborated that cause increased vascular permeability, chemotaxis, and opsonization.

Complement system acts as the bridge between innate and adaptive immune system. This concept is due to the fact that complement proteins can be activated directly by antigen-antibody complexes.

Primary Functions

There are three main effects of complement: 1.lysis of cells such as bacteria, allografts, and tumor cells; 2.generation of mediators that participate in inflammation and attract neutrophils; and 3.opsonization – enhancement of phagocytosis.

C3b is the central molecule of the complement cascade. It has two core functions: 1.it combines with other complement components to generate C5 convertase, the enzyme that leads to the production of the  membrane attack complex (first it adhere to the surface of the targets); and 2.it opsonises bacteria because phagocytes have receptors for C3b on their surface.

How to activate?

In the classic pathway, antigen-antibody complexes activate C12 to form a protease and thereafter the complement cascade starts. In the lectin pathway,  MBL (mannas-binding lectin/mannose-binding protein) binds to the surface of microbes bearing mannan. This activates proteases associated with MBL that activates complement cascade. In the alternative pathway, many unrelated cll surface substances can initiate the process by binding C3 and factor B. This complex is cleaved by a protease and finally the complement cascade initiates.

Other Mediators

  • Platelet-Activating Factor (PAF)

PAF is a phospholipid-derived mediator that was discovered as a factor that caused platelet aggregation, but it is now known to have multiple inflammatory effects. A variety of cell types, including platelets themselves, basophils, mast cells, neutrophils, macrophages, and endothelial cells, can elaborate PAF, in both recreated and cell-bound forms. In addition to platelet aggregation, PAF causes vasoconstriction and bronchoconstriction, and at low concentrations it induces vasodilation and increased ventral permeability.

  • Products of Coagulation

Protease-activated receptors (PARs) are activated by thrombin (converting fibrinogen to fibrin), and are expressed on platelets and leukocytes.

  • Kinins

Kinins are vasoactive peptides derived from plasma proteins called kininogens, by the action of specific proteases called kallikreins. The enzyme kallikrein cleaves a plasma glycoprotein precursor, high-molecular-weight kininogen, to produce bradykinin, a substance that increases vascualar permeability and causes contraction of smooth muscle, dilation of blood vessels, and pain when injected into the skin. These effects are similar to those of histamine. The action of bradykinin is short-lived, because it is quickly inactivated by an enzyme called kininase.

  • Neuropeptides

Neuropeptides are secreted by sensory nerves and various leukocytes, and may play a role in the initiation and regulation of inflammatory responses. These small peptides, such as substance P and neurokinin A, are produced in the central and peripheral nervous systems. Substance P has many biologic functions, including the transmission of pain signals, regulation of blood pressure, stimulation of hormone secretion by endocrine cells, and increasing vascular permeability.