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Role of Inflammatory Mediators in Asthma

By: Pharma Tips | Views: 5417 | Date: 04-Jul-2011

A. Cellular Origin of Mediators B. Synthesis and Metabolism C. Mediator Receptors D. Mediator EffectsE. Involvement of Mediators in Asthma

A. Cellular Origin of Mediators.B. Synyhesis and Metabolism.C. Mediator Receptors.D. Mediator Effects.E. Involvement of mediators In Asthma.F. Chronic Inflammation.G. Transcription Factors.



ROLE  OF  INFLAMMATORY MEDIATORS  IN  ASTHMA:- 

I. INTRODUCTION:-

A. Cellular Origin of Mediators.
B. Synyhesis and Metabolism.
C. Mediator Receptors.
D. Mediator Effects.
E. Involvement of mediators In Asthma.
F. Chronic Inflammation.
G. Transcription Factors.

Synthesis & Metabolism ,Receptors & Role Of The Inflammatory Mediators in Asthma:-

II. AMINE MEDIATORS:-

A. Histamine.
B. Serotonin (5-Hydroxytryptamine).
C. Adenosine.

III. LIPID DERIVED MEDIATORS:-

A. Prostanoids.
B. Leukotrienes.
C. Platelet-Activating Factor.
D. Other Lipid Mediators.

IV.PEPTIDE MEDIATORS:-

A. Bradykinin.
B. Tachykinins.
C. Calcitonin Gene-Related Peptide.
D. Endothelins.
E. Complement.


V. SMALL MOLECULES:-

A. Reactive Oxygen Species.

VI. CYTOKINES:-

A. Lymphokines:-
1. Interleukin-2.
2. Interleukin-3.
3. Interleukin-4.
4. Interleukin-5.
5. Interleukin-13.
6. Interleukin-16.
7. Interleukin-17
B. Proinflammatory Cytokines:-
1. Interleukin-1.
2. Tumor necrosis factor.
3. Interleukin-6.
4. Interleukin-11.
5. Granulocyte-macrophage colony-stimulating factor.
6. Stem cell factor.
C. Inhibitory Cytokines:-
1. Interleukin-10.
2. Interleukin-1 receptor antagonist.
3. Interferon.
4. Interleukin-12.
5. Interleukin-18.
D. Growth Factors:-
1. Platelet-derived growth factor.
2. Transforming growth factor.
3. Fibroblast growth factor.
4. Epidermal growth factor.
5. Insulin-like growth factor.

VII. CHEMOKINES:-

A. CC Chemokines.
B. CXC Chemokines.

VIII. PROTEASES:-


INTRODUCTION
A. Cellular Origin of Mediators 
Many inflammatory cells are recruited to asthmatic airways or are activated in situ. These include mast cells, macrophages, eosinophils, T lymphocytes, dendritic cells, basophils, neutrophils, and platelets. Airway epithelial cells, smooth muscle cells, endothelial cells, and fibroblasts are all capable of synthesizing and releasing inflammatory mediators.  Indeed, these cells may become the major sources of inflammatory mediators in the airway, and this may explain how asthmatic inflammation persists even in the absence of activating stimuli.(12)
B. Synthesis and Metabolism 
Many of the key 5-Lipoxygenase (5-LO)b inhibitors, which inhibit the synthesis of leukotrienes (LTs), have already been shown to have beneficial effects in the control of clinical asthma and are now available for clinical use.(13)
C. Mediator Receptors 
The receptors for many inflammatory mediators have the typical seven-transmembrane domain structure that is expected for G protein-coupled receptors. However, receptors for cytokines and growth factors have markedly different structures, and usually two or more subunits are involved. For noncytokine mediators, inflammatory receptors are often coupled, through G proteins (Gq and Gi), to phosphoinositide (PI) hydrolysis, but it is increasingly recognized that other pathways may also be activated, including the complex mitogen-activated protein (MAP) kinase pathways that are involved in more long term effects of mediators. Cytokine receptors signal through complex pathways, including MAP kinases and other protein kinases, that result in the activation of transcription factors.(14)
D. Mediator Effects
Inflammatory mediators produce many effects in the airways, including bronchoconstriction, plasma exudation, mucus secretion, neural effects, and attraction and activation of inflammatory cells. Although the acute effects of mediators have been emphasized, there is increasing recognition that mediators may result in long-lasting structural changes in the airways that are also mediated by the release of inflammatory mediators. These changes may include fibrosis resulting from the deposition of collagen, which is seen predominantly under the epithelium even in patients with mild asthma. The airway smooth muscle layer is also thickened in asthma, and this is likely the result of increases in the number of smooth muscle cells (hyperplasia) and increases in their size (hypertrophy). There may be proliferation of airway vessels (angiogenesis) and of mucus-secreting cells.(15,16)
E. Involvement of Mediators in Asthma 
The best evidence for the involvement of a mediator in asthma is obtained with the use of specific blockers. These may be drugs that block the synthesis of the mediators (e.g., 5-LO inhibitors) or drugs that block their receptors (e.g., antihistamines). Use of new and selective mediator blockers has enormously increased our understanding of the individual mediators and also of asthma itself.
F. Chronic Inflammation 
This chronic inflammation may result in structural changes in the airway, such as fibrosis (particularly under the epithelium), increased thickness of the airway smooth muscle layer (hyperplasia and hypertrophy), hyperplasia of mucus-secreting cells, and new vessel formation (angiogenesis).(17) 
G. Transcription Factors
The transcription factors include nuclear factor-B (NF-B) and activator protein-1 (AP-1), which are universal transcription factors that are involved in the expression of multiple inflammatory and immune genes and may play a key role in amplifying the inflammatory response. Other transcription factors, such as nuclear factor of activated T cells (NF-AT), are more specific and regulate the expression of a restricted set of genes in particular types of cell; NF-AT regulates the expression of interleukin (IL)-2 and IL-5 in T lymphocytes.(18,19)


AMINE MEDIATORS

A.Histamine
Histamine[2-(4-imidazole) ethylamine] was the first mediator implicated in the pathophysiological changes of asthma.
1.SYNTHESIS & METABOLISM.
Histamine is synthesized and released by mast cells in the airway wall and by circulating and infiltrating basophils. Histamine is formed by decarboxylation of the amino acid histidine by the enzyme L-histidine decarboxylase, which is dependent on the cofactor pyridoxal-5'-phosphate. Histamine is stored in granules within mast cells and basophils.(20)
2. RECEPTORS.
Three types of histamine receptors. Both H1 and H2 receptors have been cloned. Both have the seven-transmembrane domain motif typical of G proteincoupled receptors. A third histamine receptor subtype, termed H3,this receptor acts as an inhibitory autoreceptor in the central nervous system.(21)
a. H1 receptors.
IgE-dependent anaphylaxis in human lung causes increases in both cyclic adenosine monophosphate (AMP) and cyclic guanosine monophosphate (GMP) levels.H1 receptors are coupled to PI turnover, with release of intracellular calcium ions. Thus transfected H1 receptors are coupled to a rise in the intracellular calcium ion concentration ([Ca2+]i). In airway smooth muscle cells, the contractile response to histamine is partly reduced by removal of extracellular Ca2+ and by treatment with calcium channel blockers. This suggests that the bronchoconstriction response to histamine is partly mediated by opening of voltage-dependent calcium channels.(22) 
b. H2 receptors.
H2 receptors are present in the airways.Histamine stimulates an increase in cyclic AMP levels in lung fragments indicating that H2 receptors are positively coupled to adenylyl cyclase in lung.(23)
c. H3 receptors. 
H3-receptors can be used to establish that these receptors are involved in the feedback control of histamine synthesis and release, and to demonstrate their distribution in the brain and peripheral tissues.(24)

3. ROLE IN ASTHMA
Effects on airways.
a. AIRWAY SMOOTH MUSCLE. 
Histamine stimulates PI hydrolysis in airway smooth muscle. Histamine also increases the concentration of inositol-1,4,5-trisphosphate (IP3) in airway smooth muscle, In cultured human airway smooth muscle cells, histamine increases [Ca2+]i via an increase in IP3 levels. 
Histamine contracts both central and peripheral airways with a more potent effect on peripheral airways. (25,26)
b. VESSELS.
In human skin, histamine causes a vasodilating response (flare) that is mediated by H1 receptors. Human bronchial vessels are relaxed by low concentrations of histamine but are constricted by high concentrations. Both effects are blocked by mepyramine, indicating that H1 receptors are involved. It is likely that the vasodilating response is the result of the release of NO from endothelial cells and that the vasoconstricting effect is the result of the direct action of histamine on vascular smooth muscle H1 receptors.(27)
c. SECRETIONS. 
Histamine stimulates the secretion of mucus glycoproteins in human airways Histamine induces a rise in secretory IgA and lactoferrin, which implies active glandular secretion, suggesting that H1 receptors are involved.
Histamine also increases chloride ion transport in canine tracheal epithelial cells, histamine increases [Ca2+]i and releases a variety of mediators, including interleukin (IL)-6 and fibronectin.Histamine also increases the expression of intercellular adhesion molecule-1 (ICAM-1) and the surface marker HLA-DR in primary cultured human bronchial epithelial cells. This effect is largely mediated by H1 receptors..(28,29) 

B. Serotonin (5-Hydroxytryptamine) 

1. SYNTHESUS & METABOLISM. 
Serotonin is formed by decarboxylation of tryptophan (obtained in the diet) and is stored in secretory granules. Serotonin is present in mast cell granules from rodents but not humans. The major source of serotonin in humans is platelets, but serotonin is also found in neuroendocrine cells of the respiratory tract.

2. RECEPTORS.
There are up to seven types of 5-HT receptors, each with several subtypes.

3. Effects on airways. 
The receptor mediating this response appears to be a 5-HT3 receptor. Serotonin has a blocking effect on sodium channels in human airway epithelial cells.(30)

C. Adenosine

1. SYNTHESIS & METABOLISM
Adenosine is a purine nucleoside that is produced by dephosphorylation of 5'-AMP by the enzyme 5'-nucleotidase and is liberated intracellularly by cleavage of the high energy bonds of adenosine triphosphate, adenosine diphosphate, and cyclic 5'-AMP. This conversion is performed by extracellular 5'-nucleotidase. Mast cells are a likely source of adenosine in this situation, because these cells have been capable of releasing adenosine in response to IgE cross-linking and other stimuli for mast cell activation.

2. RECEPTORS
Receptors include the A1, A2a, A2b, and A3 receptor subtypes. Interaction of adenosine with these receptors leads to either inhibition of adenylyl cyclase (A1), stimulation of adenylyl cyclase (A2a and A2b), or activation of phospholipase C (A3). The A1 receptor is expressed in lung tissue and, in particular, A1 receptors on human epithelial cells. A2a, A2b, and A3 receptors are expressed in several tissues, including lungs, and in mast cells and fibroblasts.(31,32)

3. ROLE IN ASTHMA
Effects on airways.

a. AIRWAY SMOOTH MUSCLE. 
The brononstricting effects of adenosine are indirect, resulting from the activation of mast cell degranulation, because adenosine causes histamine release from mast cells.(33)

LIPID DERIVED MEDIATORS

A. Prostanoids 
Prostanoids include PGs and thromboxane (Tx), which are generated from arachidonic acid, usually by the action of COX (PGH2 synthase).
1.SYNTHESIS & METABOLISM.
Prostanoids are generated from arachidonic acid by two forms of COX. COX-1 is constitutive and is responsible for basal release of prostanoids, whereas COX-2 is inducible by inflammatory stimuli, such as endotoxin and pro inflammatory cytokines, and its induction is inhibited by glucocorticoids. Both COX-1 and COX-2 are expressed in human lung. Human airway epithelial cells basally express COX-1, whereas COX-2 is induced by IL-1 and TNF-and is enhanced by NO. Isoprostanes are generated by lipid peroxidation of arachidonic acid by oxidative stress.(34,35,36)
2. RECEPTORS.
Prostanoid receptors are classified according to the prostanoid that causes selective activation;PGE2 preferentially activates EP receptors, PGI2 (prostacyclin) activates IP receptors, PGF2 activates FP receptors, PGD2 activates DP receptors, and Tx activates TP receptors. Within each receptor type there may be distinct subtypes; the EP receptor has at least four subtypes, which are differentially expressed in er algesic responses, whereas EP2 and EP4 receptors mediate smooth muscle relaxation in different cell types. EP1 receptors mediate activation responses and are involved in hypoxing responses and EP3 receptors modulate neurotransmitter release. In airway smooth muscle, several constrictor PGs (PGD2, PGF2, and 8-epi-PGF2) work through activation of TP receptors.(37,38)
3. ROLE IN ASTHMA
Effects on airways.
a. AIRWAY SMOOTH MUSCLE.
PGE2 relaxes human airway smooth muscle via EP receptors(Excitatory Post synaptic). The relaxation response to PGE2 in human airways is mediated by EP2 receptors.(39)
b. VESSELS. 
PGE2 and PGI2 are vasodilators and therefore should theoretically increase leakage in asthmatic airways.
c. NERVES.
PGE2 inhibits cholinergic nerve constriction of human airways in at  lower concentrations than those that cause bronchoconstriction.This may be mediated by EP1 receptors. In addition, PGE2a inhalation increases the sensation of dyspnea. PGF2 also induces coughing.(40,41)

B. Leukotrienes 
1. SYNTHESIS & METABOLISM.
LTs are potent lipid mediators produced by arachidonic acid metabolism in cell or nuclear membranes. They are derived from arachidonic acid, which is released from membrane phospholipids via the activation of phospholipase A2.Arachidonic acid is subsequently metabolized by the enzyme 5-LO, to produce LTs. Several types of airway cells, including mast cells, eosinophils, macrophages, neutrophils, and epithelial cells, can synthesize LTs in response to a variety of stimuli. LTB4, synthesized predominantly by LTA4 hydrolase in neutrophils, is an extremely potent activator of neutrophils, causing aggregation, chemotaxis, and degranulation.(42,43)
2. RECEPTORS.
The BLT receptors are activated by LTB4.Cys-LTs act via cys-LT receptors, of which two types have been pharmacologically characterized. Cys-LT1 receptors mediate all of the known airway effects of cys-LTs in human cells. A second receptor type, the cys-LT2 receptor responses to certain LT antagonists.(44,45)

3. ROLE IN ASTHMA

Effects on airways.

a. AIRWAY SMOOTH MUSCLE. 
Cys-LTs are very potent contractile agents for human bronchi being approximately 1000 times more potent than histamine, and they elicit this effect via activation of cys-LT1receptors.Cyst-LTs may also stimulate airway smooth muscle by Tx(46)

b SECRETION.
Cys-LTs increase mucus secretion, both directly via effects on goblet cells and sub mucosal gland cells  and indirectly via the activation of airway nerves, leading to reflex secretion from sub mucosal glands.(47)

C. Platelet-Activating Factor 
PAF has long been implicated in the pathophysiological mechanisms of asthma, because exogenous PAF closely mimics many of the clinical features of asthma, including airway hyperresponsiveness.

1.SYNTHESIS & MTABOLISM. 
PAF is an ether-linked phospholipid (1-O-alkyl-sn-glycero-3-phosphocholine) that was first described as a substance released from IgE-stimulated basophils. The synthesis of PAF occurs in a wide variety of inflammatory cells, including platelets, neutrophils, basophils, macrophages, and eosinophils.

The major enzyme responsible for the catabolism of PAF is PAF acetylhydrolase, a PAF-specific esterase that cleaves the acetyl group at the sn-2-position, producing lyso-PAF. PAF acetylhydrolase was initially described as being abundant in human plasma and was later shown to be associated with low density lipoproteins.(48,49)

2. RECEPTORS.
A PAF receptor in human platelets and leukocytes and shown to be a typical G protein-linked receptor with seven trans membrane domains.Substitution of the Cys90, Cys95, or Cys173 residues in the PAF receptor with alanine or serine yields mutant receptors that do not bind PAF.The cell signaling pathways initiated by PAF interactions with its receptor are well characterized and include increases in [Ca2+]i, increases in IP3 and diacyl glycerol levels, and induction of cell cycle-active genes, such as fos, jun, and egr-1. PAF also activates the transcription factor AP-1 in bronchial epithelial cells. The PAF receptor undergoes homologous desensitization by phosphorylation of cytoplasmic tail sites in the receptor molecule , and related lipids such as PAGPC can also desensitize the classical PAF receptor.(50,51)

3. ROLE IN ASTHMA
Effects on airways.

a. AIRWAY SMOOTH MUSCLE.
PAF has little direct effect on human airway smooth muscle contraction in but may elicit constriction through the release of other mediators. PAF produces acute broncho constriction when inhaled by patients with asthma.

b. VESSELS.
PAF has potent effects on vascular smooth muscle and elicits hypotension in several species.PAF is very potent in causing vascular engorgement and increased vascular permeability in the airways, leading to plasma exudation of protein-rich fluid into the airway lumen.(52)

c. NERVES. 
PAF has ability  to induce increased responsiveness of the nose and airways (reviewed above) is that it functions via the activation of airway nerves. PAF up-regulates the expression of H1 receptor mRNA in trigeminal ganglia and stimulates the transcription factor AP-1 in human neuroblastoma cells.(53)

D. Other Lipid Mediators 

1. SYNTHESIS & METABOLISM.
Several other lipid mediators, including hydro peroxy eicosate traenoic acid (HPETEs), mono-and di-HETEs, and lipoxins (LXs),Most of these substances are metabolic products of the 15-LO enzyme, which catalyzes the insertion of molecular oxygen at the carbon atom at position 15 in the arachidonic acid molecule.15-LO demonstrated in human tracheal epithelium, eosinophils, endothelial cells, and monocytes.15-LO is expressed in airway epithelium and eosinophils. LXs (LO interaction products), of which the most prevalent is LXA4, are produced by interactions between 15-LO and 5-LO or between 12-LO and 5-LO.(54.55)

2. RECEPTORS.
Little is known regarding receptors for 15-LO products, and it is not clear whether there are distinct receptors for these HETEs and HPETEs. Specific LXA4 receptors have been identified in murine and human cells.(56)

3. ROLE IN ASTHMA.
Effects on airways.
Both mono- and di-HETEs are chemotactic for neutrophils and eosinophils. LXs have been demonstrated to contract airway smooth muscle and to activate PKC. LXA4 inhibits neutrophil and eosinophil activation by N-formyl-methionyl-leucyl-phenylalanine and PAF, respectively, and inhibits adhesion of leukocytes, suggesting that it has an anti-inflammatory role. LXA4 also inhibits cholinergic neurotransmission in airways, an effect that may be mediated by release of NO.(57)

PEPTIDE MEDIATORS
Several peptides, including bradykinin, tachykinins, CGRP, endothelins (ETs), and complement, are involved in asthma. 
A. Bradykinin 
1.SYNTHESIS & METABOLISM. 
Kinins are vasoactive peptides that are formed, during the inflammatory response, from the  2-globulins high molecular weight (HMW) and low molecular weight (LMW) kininogens, by the action of kininogenases. Kininogenases include plasma kallikrein and tissue kallikrein. HMW and LMW kininogens are produced from the same gene (containing 11 exons and 10 introns) as a consequence of alternative splicing. Both kininogens are synthesized in the liver. HMW kininogen is present only in plasma, whereas LMW kininogen also occurs in tissues. Two kinins are formed in humans, i.e., the nonapeptide bradykinin (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg), which is generated from HMW kininogen, and the decapeptide lysyl-bradykinin (kallidin), which is generated from LMW kininogen. Kallidin is rapidly converted to bradykinin by the enzyme aminopeptidase-N. and it is likely that bradykinin is formed, by the action of plasma and tissue kallikreins, in plasma that has been exuded from the inflamed airways. (58,59)
2. RECEPTORS. 
At least two subtypes of bradykinin receptors are recognized B1,[des-Arg10]-lysyl-bradykinin > [des-Arg9]-bradykinin = lysyl-bradykininbradykinin;B2,bB1receptors are selectively activated by lysyl-bradykinin (kallidin) and [des-Arg9]-bradykinin and are inducible by inflammatory signals. The effects of bradykinin on airways are mediated by B2 receptors, and there is no evidence for functional B1 receptors in the airways.(60)
3. ROLE IN ASTHMA.
Effects on airways.
a. AIRWAY SMOOTH MUSCLE.
bradykinin is only a weak constrictor of proximal human airways, suggesting that its potent bronchoconstricting effect in asthmatic patients is mediated indirectly, bradykinin is more potent in constricting peripheral human airways partly via direct stimulation of B2 receptors on airway smooth muscle cells and partly via the release of Tx. Bradykinin contracts airway smooth muscle (60,61) 

b.VESSES.
Bradykinin is a potent inducer of airway microvascular leakage and causes prolonged leakage at all airway levels. This is partly mediated by the release of PAF. The immediate leakage response to bradykinin is partly mediated by the release of neuropeptides (probably SP) from airway sensory nerves. Bradykinin is a potent vasodilator of bronchial vessels and causes an increase  in airway blood flow.(62) 
c. SECRETIONS
Bradykinin stimulates airway mucus secretion from human submucosal glands in and these effects are mediated by B2 receptors , presumably indicating a direct effect of bradykinin on submucosal glands. Bradykinin also stimulates the release of mucus glycoproteins from human nasal mucosa. Bradykinin stimulates ion transport in airway epithelial cells, which is mediated by the release of PGs. The effects of bradykinin on epithelial cells are mediated by B2 receptors.(63,64,65) 

B. Tachykinins 
Airway sensory nerves have the capacity to release neuropeptides, particularly the tachykinins SP and NKA, as well as CGRP, which may have proinflammatory effects in the airway. Because airway sensory nerves are activated in asthma.
1.SYNTHESIS & METABOLISM.
SP and NKA are localized to sensory nerves in the airways of several species. SP-immunoreactive nerves are sparse in human airways. SP-immunoreactive nerves fibers also innervate parasympathetic ganglia, suggesting a sensory input that may modulate ganglionic transmission and thus result in local reflexes. SP in the airways is localized predominantly to capsaicin-sensitive unmyelinated nerves. Tachykinins are derived from preprotachykinins (PPTs) that are expressed in nodose and jugular ganglia.There are three PPT genes:  -PPT codes for SP alone, -PPT codes for SP and NKA, and  -PPT codes for SP, NKA, and novel,amino-terminally extended form of NKA termed NP- .Tachykinins may be synthesized in nonneuronal cells, such as macrophages.Human macrophages express  -PPT, and SP is released from these cells by capsaicin.(66,67)
2. RECEPTORS.
At least three subtypes of tachykinin receptors :SP acts preferentially at NK1 receptors, NKA at NK2 receptors, and NKB at NK3 receptors. Tachykinin receptors are differentially expressed and are also subject to differential regulation, for example by inflammatory stimuli. Tachykinins are typical G protein-coupled receptors and lead to increased PI hydrolysis, with an increase in the release of intracellular Ca2+, IP3, and diacylglycerol.NK1 receptors are localized to bronchial vessels, epithelial cells, and submucosal glands, whereas NK2 receptors are predominantly localized to airway smooth muscle.(68)
3. ROLE IN ASTHMA
Effects on airways.
Tachykinins have many different effects on the airways that may be relevant to asthma, and these effects are mediated by NK1 and NK2 receptors. There is little evidence for the involvement of NK3 receptors.
a. AIRWAY SMOOTH MUSCLE.
Tachykinins constrict human airway smooth muscle in via NK2 receptors. The contractile response to NKA is significantly greater in smaller human bronchi than in more proximal airways, indicating that tachykinins may have a more important constricting effect in peripheral airways, whereas cholinergic constriction tends to be more pronounced in proximal airways. NP-  is also a potent constrictor of human airways and acts via NK2 receptors. (69,70) 
b. VESSELS. 
Tachykinins have potent effects on airway blood flow. In canine and porcine trachea, both SP and NKA because marked increases in blood flow Tachykinins also dilate canine bronchial vessels probably via an endothelium-dependent mechanism.Tachykinins also regulate bronchial blood flow; stimulation of the vagus nerve causes vasodilation mediated by the release of sensory neuropeptides, and it is likely that CGRP as well as tachykinins are involved.(71,72)
c. SECRETIONS.
SP stimulates mucus secretion from submucosal glands (mediated by NK1 receptors) human airways. SP is likely to mediate the increases in goblet cell discharge after vagus nerve stimulation.(73) 

C. Calcitonin Gene-Related Peptide 

1. SYNTHESIS & METABOLISM.
CGRP is stored and localized with SP in afferent nerves. CGRP is localized to human airways.CGRP is found in trigeminal, nodose-jugular, and dorsal root ganglia and also in neuroendocrine cells of the lower airways. The metabolism of CGRP is less clear, metabolism of CGRP by NEP appears to liberate a peptide fragment that has eosinophil chemotactic activity.(74,75)

2. RECEPTORS
CGRP acts on specific receptors that are coupled (via Gs) to adenylyl cyclase, resulting in an increase in intracellular cyclic AMP concentrations. CGRP receptors subtypes:Gs,Gi,G0,Gq.CGRP receptors have are predominantly located in bronchial vascular smooth muscle, rather than airway epithelium.(76,77)

3. ROLE IN ASTHMA.
Effects on airways.
a. AIRWAY SMOOTH MUSCLE.
CGRP causes constriction of human bronchi. This because CGRP increases cyclic AMP levels. If any, CGRP receptors in airway smooth muscle in human airways and  then paradoxical bronchoconstriction response may be mediated indirectly in human airways.(78)
b. VESSELS
CGRP is an effective dilator of human pulmonary vessels in and acts directly on receptors in vascular smooth muscle. So CGRP may be the predominant mediator of arterial vasodilation and increased blood flow in response to sensory nerve stimulation in the bronchi.(79)

D. Endothelins 
ETs are potent constrictor peptides that were released from endothelial cells. There is now considerable evidence that they are involved in the pathophysiological mechanisms of asthma.(80,81)
1. SYNTHESIS & METABOLISM.
There are three ET peptides, and each is encoded by a distinct gene, which codes for the precursor peptide. Prepro-ET-1 is cleaved to a 38-amino acid intermediate form termed big ET-1 or pro-ET-1. Pro-ET-1 is rapidly cleaved by a specific enzyme, termed ET-converting enzyme (ECE), to form mature ET-1. ECE is a neutral metalloendopeptidase.(82)
2.  RECEPTORS
Two distinct receptors, with structures typical of G protein-coupled receptors, they exhibit approximately 60%.The existence of a third ET receptor, which is selective for ET-3 (ETC receptor), has been proposed ,there is little conclusive evidence for this in human tissues. ETA and ETB receptors are expressed in lung.(83,84)
3.  ROLE IN ASTHMA
Effects on airways.
a. AIRWAY SMOOTH MUSCLE. 
ET-1 and ET-2 are potent constrictors of human airway smooth muscle, being even more potent than LTD4.ET-1 appears to cause a maximal contractile response. ET-1 may produce a prolonged contractile response in human airway smooth muscle by activating PKC. Rapid degradation of ET-3 by epithelial  NEP. ET-3-mediated contraction of human airways.(85,86)
b. VESSELS.
ET-1 constricts human bronchial arteries,but its effects on airway microvascular leakage are conflicting.(87)

E. Complement 

1. SYNTHESIS & METABOLISM.
The complement system contains a series of 30 distinct circulating proteins:-proteolytic proenzymes, nonenzymatic components that form functional enzymes when activated, and receptors. However, there are several by-products generated during the activation of the complement cascade that have proinflammatory activity and therefore have the potential to be involved in asthma. The larger fragments of C3 and C4 (i.e., C3b and C4b) are involved in a range of biological activities, including opsonization, phagocytosis, and immunomodulation.(88,)

2. RECEPTORS
There are distinct receptors for C3a and C5a.Both is members of the G protein-coupled receptor superfamily.(88)

3. ROLE IN ASTHMA
Effects on airways. 
C3a and C5a induce airway smooth muscle contraction and chemotaxis of leukocytes, including eosinophils. Both C3a and C5a are potent stimulants of eosinophil degranulation. C5a is also a potent chemoattractant of human monocytes and may therefore be involved in recruitment of macrophages into asthmatic airways.(89,90)

SMALL MOLECULES
REACTIVE OXYGEN SPECIES.
1. SYNTHESIS & METABOLISM.
Many inflammatory and structural cells that are activated:eosinophils, macrophages, mast cells, and epithelial cells, produce ROS.Superoxide anions are generated by NADPH oxidase and then are converted to hydrogen peroxide by superoxide dismutases (SODs). Hydrogen peroxide is then degraded to water by catalases. Superoxide and hydrogen peroxide may interact in the presence of free iron to form the highly reactive hydroxyl radical. Superoxide may also combine with NO to form peroxynitrite, which also generates hydroxyl radicals.Oxidative stress describes an imbalance between ROS and antioxidants. The major intracellular antioxidants in the airways are catalase, SOD, and glutathione, which is formed by the selenium-dependent enzyme glutathione peroxidase. Extracellular antioxidants include the dietary antioxidants vitamin C (ascorbic acid) and vitamin E ( -tocopherol), uric acid, and lactoferrin. Oxidant stress activates the inducible enzyme heme oxygenase-1, which converts heme and hemin to biliverdin, with the formation of carbon monoxide. Biliverdin is converted, by bilirubin reductase, to bilirubin, which is a potent antioxidant.(91,92,93)
2. ROLE IN ASTHMA
Effects on airways.
a. AIRWAY SMOOTH MUSCLE.
ROS may damage airway epithelium, resulting in increased epithelial shedding and increased bronchoconstriction responses, hydrogen peroxide induces an increase in the responsiveness of human airways.(94)
B. Nitric Oxide 
There is increasing evidence that endogenous NO plays a key role in physiological regulation of airway functions and is implicated in airway diseases, including asthma.
1. SYNTHESIS & METABOLISM.
NO is a gas that is derived from the amino acid L-arginine by the enzyme NOS, of which at least three isoforms exist.There are two cNOS forms; one was first described in brain and is localized to neural tissue [neuronal NOS (nNOS) or NOSI], and the other is localized to endothelial cells [endothelial NOS (eNOS) or NOSIII], although it has become apparent that both enzymes are also expressed in other cells, such as epithelial cells. Both enzymes are activated by increases in [Ca2+]i and produce small amounts of NO, which serve a local regulatory function. In contrast, iNOS (NOSII) is not normally expressed but is induced by inflammatory cytokines and endotoxin.
In asthmatic airways, there is increased immunocytochemical staining for iNO, which is localized predominantly to airway epithelial cells ,and there is also localization to inflammatory cells, including macrophages and eosinophils .NO may be produced by several types of cells in a human epithelial cell line (A549) and in pneumocytes, oxidants and ozone increase iNOS expression. This is associated with activation of NF- B, which is involved in the transcription of many inflammatory and immune genes.NF- B is of critical importance in increasing the transcription of the iNOS gene and may be activated in several types of pulmonary cells by proinflammatory cytokines. (95,96)
2. RECEPTORS
NO diffuses into cells and activates soluble guanylyl cyclase, resulting in an increase in the formation of cyclic GMP. In airway smooth muscle, cyclic GMP causes relaxation.(97)
3. ROLE IN ASTHMA.
Effects on airways.

a. AIRWAY SMOOTH MUSCLE 
NO and NO donor compounds relax human airway smooth muscle via activation of guanylyl cyclase and increases in cyclic GMP levels. NO may, however, be the major neurotransmitter of bronchodilating nerves in human airways. In proximal human airways, there is a prominent inhibitory NANC(i-NANC)bronchodilating neural mechanism, because it is the only endogenous bronchodilating pathway in human airways. The neurotransmitter of this i-NANC pathway in human airways is NO. Furthermore , i-NANC stimulation of human airways results in an increase in cyclic GMP levels without any increase in cyclic AMP levels.(97,98)
b. VESSELS.
NO is a potent vasodilator in the bronchial circulation and may play an important role in regulating airway blood flow, as in the pulmonary circulation. (99)
c. SECRETIONS. 
L-NAME increases basal airway mucus secretions, suggesting that NO produced by cNOS normally inhibits mucus secretion.However, NO donors increase mucus secretion in human airways.NO may also be important in regulating mucociliary clearance, because a NOS inhibitor decreases ciliary beat frequency in bovine airway epithelial cells.(100)

CYTOKINES
CYTOKINE RECEPTORS
The receptors for many cytokines have been grouped into superfamilies.
a. CYTOKINE RECEPTOR SUPERFAMILY.
This largest receptor superfamily includes IL-2 receptor  -and  -chains, IL-4 receptor, IL-3 receptor  -and  -chains, IL-5  -and  -chains, IL-6 receptor, gp130, IL-12 receptor, and GM-CSF receptor.The extracellular regions of the cytokine receptor family contain combinations of cytokine receptor domains, fibronectin type III domains, and usually C2 Ig constant region-like domains. Some members are composed of a single polypeptide chain that binds its ligand with high affinity. For other receptors, there may be more than one binding site for the ligand (typically sites with high and low binding affinities).Some of these subunits are shared by more than one cytokine receptor, giving rise to heterodimeric structures. Such examples include (a) receptors sharing the GM-CSF receptor  -chain (IL-3, IL-5, and GM-CSF); (b) receptors sharing the IL-6 receptor  -chain, gp130 (IL-6, leukemia inhibitory factor, and oncostatin M); and (c) receptors sharing the IL-2 receptor  -chain (IL-2, IL-4, IL-7, and IL-15). 
b. IMMUNOGLOBULIN SUPERFAMILY.
Cytokine receptors with Ig superfamily domains in their extracellular sequences include IL-1, IL-6, PDGF, and GM-CSF receptors. The Ig domains are characterized by a structural unit of approximately 100 amino acids, with a distinct folding pattern known as the Ig fold.
c. PROTEIN KINASE RECEPTOR SUPERFAMILY.
These receptors have glycosylated, extracellular, ligand-binding domains, a single transmembrane domain, and an intracellular, tyrosine kinase catalytic domain. The superfamily includes receptors for growth factors such as PDGF, EGF, and FGF. 
d. INTERFERON RECEPTOR SUPERFAMILY.
This group includes the IFN-a/B receptor, IFN-Y receptor, and IL-10 receptor. They are single-transmembrane domain glycoproteins that are characterized by either one (IFN- and IL-10 receptors) or two (IFN- receptors) homologous extracellular regions. Signal transduction involves phosphorylation and activation of Janus protein kinase and tyrosine kinase 2 protein tyrosine kinases. 
e. NERVE GROWTH FACTOR RECEPTOR SUPERFAMILY.
These cytokine receptors include the nerve growth factor receptor, TNF receptor-I and TNF receptor-II .These are characterized by three or four cysteine-rich repeats of approximately 40 amino acids in the extracellular part of the molecule. The mode of signal transduction has not been elucidated. 
f. SEVEN- TRANSMEMBRANE G PROTEIN-RECEPTOR. 
These receptors include the chemokine receptors, which have a characteristic structure of a relatively short, acidic, extracellular, amino-terminal sequence followed by seven transmembrane domains with three extracellular and three intracellular loops. The receptors are coupled to heterotrimeric G proteins, which induce PI phosphate hydrolysis and activate kinases, phosphatases, and ion channels.

B. Lymphokines 
Lymphokines are cytokines that are produced by T lymphocytes.They play an important role in immunoregulation.

1. Interleukin-2.
a. SYNTHESIS AND RELEASE.
Activated T cells, particularly Th0 and Th1 T cells, are major sources of IL-2.IL-2 is secreted by antigen-activated T cells 4 to 12 h after activation, accompanied later by up-regulation of high affinity IL-2 receptors on the same cells. Binding of IL-2 to IL-2 receptors induces proliferation of T cells, secretion of cytokines, and enhanced expression of receptors for other growth factors, such as insulin. IL-2 can also be produced by eosinophils and by airway epithelial cells.(101,102) 

b. RECEPTORS.
The IL-2 receptor complex is composed of three chains( ,  , and  ) and belongs to the family of hematopoietic cytokine receptors, and   -chains bind to IL-2 with low affinity, whereas the  -chain does not bind IL-2 alone. The high affinity complex is an heterotrimer, whereas and heterodimers have intermediate affinities. The  -chain, which is expressed constitutively in T lymphocytes, is essential for signal transduction, and the intracellular domain has critical sequences necessary for growth-promoting signals .The  -chain also appears to be important for signal transduction.(103,104)


c. ROLE IN ASTHMA
Effects on airways.
IL-2 stimulates the growth and differentiation of T cells, B cells, natural killer cells, lymphokine-activated cells, and monocytes/macrophages. IL-2 functions as an autocrine growth factor for T cells and also exerts paracrine effects on other T cells. IL-2 promotes the differentiation and Ig secretion of B cells. IL-2 acts on monocytes to increase IL-1 secretion, cytotoxicity, and phagocytosis.(105)

2. Interleukin-3.
a. SYNTHESIS AND RELEASE.
Activated Th cells are the predominant source of IL-3, together with mast cells.(106)
b. RECEPTORS.
The IL-3 receptor is formed by the association of a low affinity IL-3-binding  -subunit with a   -subunit, which is common to the IL-5. IL-3 binding to its receptor results in rapid tyrosine and serine/threonine phosphorylation of several cellular proteins, including the IL-3 receptor subunit itself .The human IL-3 receptor is expressed on myeloid, lymphoid, and vascular endothelial cells. It is selectively induced in human endothelial cells by TNF-, and it potentiates IL-8 secretion and neutrophil transmigration .(107,108)

ROLE IN ASTHMA.
Effects on airways. 

IL-3 is a pluripotent hematopoietic growth factor that, together with other cytokines such as GM-CSF, stimulates the formation of erythroid cell, megakaryocyte, neutrophil, eosinophil, basophil, mast cell, and monocytic lineages GM-CSF also increases the responsiveness of neutrophils to IL-3.(109)

3. Interleukin-4.

a. SYNTHESIS AND RELEASE.
IL-4 is produced by Th2-derived T lymphocytes, thymocytes, as well as eosinophils and cells of the basophil and mast cell lineages. Synthesis can be induced by stimulation of the antigen receptor on T lymphocytes and by IgE Fc receptor cross-linking in mast cells and basophils.(110)
b. RECEPTORS.
The IL-4 receptor is a complex consisting of two chains, a high affinity IL-4-binding chain(p140, -chain),which binds IL-4 and transduces its growth-promoting and transcription-activating functions ,and the IL-2 receptor  -chain (the common  -chain,  c), which amplifies signaling of the IL-4 receptor. The  -chain belongs to the cytokine receptor superfamily. A recombinant extracellular domain of the human IL-4 receptor is a potent IL-4 antagonist. The IL-2 receptor  -chain augments IL-4 binding affinity. They are also present on hematopoietic progenitor cells, mast cells, macrophages, endothelial cells, epithelial cells, fibroblasts, and muscle cells.IL-4 induces phosphorylation of the IL-4-induced phosphotyrosine substrate, which is associated with the p85 subunit of phosphatidylinositol-3 kinase and with Stat-6 and Janus protein kinase after cytokine stimulation.(111,112)
c. ROLE IN ASTHMA.
Effects on airways.
IL-4 plays an important role in B lymphocyte activation by increasing expression of class II major histocompatibility complex (MHC) molecules, as well as enhancing expression of CD23 (low affinity FcRII), CD40, and the  -chain of the IL-2 receptor. It promotes Ig synthesis by B lymphocytes and plays a central role in Ig class switching of activated B lymphocytes to the synthesis of IgG4 and IgE.IL-4 promotes the development of Th2-like CD4+ T cells and inhibits the  development of Th1-like T cells .It also enhances the cytolytic activity of CD8+ cytotoxic T cells.(113,114)

4. Interleukin-5.
a. SYNTHESIS AND RELEASE. 
IL-5 is produced by T lymphocytes of spleen cells; CD4+ and CD8+ T cells can also secrete IL-5.Transcriptional control of the human IL-5 gene involves several transcription factors, including NF-AT( nuclear factor of activated T cells).(115)
b. RECEPTORS.
The human IL-5 receptor present on eosinophils, basophils, and B lymphocytes.It consists of a heterodimer with two polypeptide chains, i.e., a low affinity binding  -chain and a nonbinding  -chain shared with the IL-3 and GM-CSF receptors .Both chains belong to the cytokine receptor superfamily The  -subunit alone is sufficient for ligand binding and is specific for IL-5, but association with the  -chain leads to a 2- to 3-fold increase in binding affinity and allows signaling to occur.Transcriptional regulation of the specific chain yields either membrane-bound or soluble forms of the receptor.(116,117)
c. ROLE IN ASTHMA.
Effects on airways.
IL-5 can influence the production, maturation, and activation of eosinophils. IL-5 acts predominantly at the later stages of eosinophil maturation and activation .IL-5 can also prolong the survival of eosinophils . On the other hand, IL-5 instilled into the airways of patients with asthma induces significant airway eosinophilia .(118)

5. Interleukin-13.
a. SYNTHESIS AND RELEASE.
IL-13 is synthesized by activated CD4+ and CD8+ T cells and is a product of Th1, Th2, and Th0-like CD4+ T cell clones .Both CD4+ and CD8+ T cell clones synthesize IL-13 in response to antigen-specific or polyclonal stimuli.(119)
b. RECEPTORS. 
There is a close similarity between IL-4 and IL-13 receptors.IL-13 receptor to suggest that the IL-4 receptor  -chain is a component of the IL-13 receptor.(120) 
c. ROLE IN ASTHMA.
Effects on aurways..
IL-13 is a potent modulator of human monocyte and B cell function.In human monocytes stimulated by lipopolysaccharide, the production of proinflammatory cytokines, chemokines, and colony-stimulating factors is inhibited by IL-13, whereas IL-1ra secretion is increased. Production of IL-1, IL-6, IL-8, IL-10, IL-12, IFN-  ,and GM-CSF from blood monocytes is inhibited whereas MIP-1  ,IL-1,and TNF-   release from human alveolar macrophages is inhibited.IL-13 inhibits the release of RANTES and IL-8 from airway smooth muscle cells .These actions of IL-13 are similar to those of IL-4 and IL-10.(121,122)

6. Interleukin-15.
a. SYNTHESIS AND RELEASE.
IL-15 is produced by both CD4+ and CD8+ T cells after activation .IL-15 mRNA is expressed in lung fibroblasts and epithelial cell lines, as well as monocytes and human blood-derived dendritic cells .(123)
b. RECEPTORS.
IL-15 uses the   - and   -subunits of the IL-2 receptor, and both chains are needed for IL-15-mediated actions. Mitogen-activated macrophages, natural killer cells, and CD4+ and CD8+ T cells express IL-15 receptor  -chains, which can bind IL-15 without requiring IL-2 receptor  - or  -chains.(124) 
c. ROLE IN ASTHMA.
Effects on airways. 
IL-15 lead to stimulation of the proliferation of T cells and lymphokine-activated killer cells. However,IL-15 can induce IL-8 and macrophage chemotactic peptide (MCP)-1 production in human monocytes .It also induces the release of soluble IL-2 receptor -chain from human blood mononuclear cells .It promotes angiogenesis in vivo .IL-15 can also activate neutrophils and delay their apoptosis .IL-15 promotes the synthesis of IL-5 from house dust mite-specific human T cell clones,an effect inhibited by the tyrosine kinase inhibitor herbimycin A.¬(125)

7. Interleukin-16.

a. SYNTHESIS AND RELEASE.
IL-16, previously known as lymphocyte chemoattractant factor. IL-16 was subsequently shown to be produced by CD8+ T cells after stimulation with histamine and serotonin. IL-16 can also be produced by epithelial cells, eosinophils and mast cells .(126,127)
b. ROLE IN ASTHMA
Effects on airways.
IL-16 has specific activities on CD4+ T cells .IL-16 selectively induces migration of CD4+ cells, including CD4+ T cells and CD4-bearing eosinophils.IL-16 acts as a growth factor for CD4+ T cells and induces IL-2 receptors and MHC class II molecules on these cells .(128)

8. Interleukin-17. 
IL-17 is a CD4+ T cell-derived cytokine that stimulates NF -B and IL-6 production in fibroblasts and co-stimulates T cell proliferation. It stimulates epithelial, endothelial, and fibroblastic cells to secrete cytokines such as IL-6, IL-8, GM-CSF, and PGE2 .In the presence of IL-17, fibroblasts can sustain the proliferation of CD34+ hematopoietic progenitors and their preferential maturation into neutrophils. IL-17 increases the release of NO in cartilage from patients with osteoarthritis, via NF B activation .(129,130)

C. Proinflammatory Cytokines
Proinflammatory cytokines are involved in most types of inflammation and appear to amplify and perpetuate the ongoing inflammatory response. They may be important in disease severity and resistance to anti-inflammatory therapy in asthma.

1. Interleukin-1.

a. SYNTHESIS AND RELEASE.
IL-1 is produced by a variety of cells, including monocytes/macrophages, fibroblasts, B cells, both Th1 and Th2-like T cell lines, natural killer cells, neutrophils, endothelial cells, and vascular smooth muscle cells. The major source of IL-1 in most tissues is stimulated monocytes/macrophages. Monocytes produce 10 times more IL-1  than IL-1 ;IL-1  is mostly cell-associated, whereas IL-1  is mostly released. Eosinophils can produce IL-1 ,whereas human epithelial cells can augment IL-1  expression when exposed to the air pollutant nitrogen dioxide .A wide variety of stimuli, including IL-1 itself ,TNF- , GM-CSF,endotoxin, and phagocytosis, can increase the expression of IL-1 in monocytes/macrophages. IL-1 production by endothelial and vascular smooth muscle cells can also be induced by IL-1, TNF- , or endotoxin.(131,132,133)
b. RECEPTORS.
Two IL-1 receptors: type I and type II receptors are transmembrane glycoproteins that bind IL-1 , IL-1 , and IL-1ra. The type I IL-1 receptor is expressed on many cells, including T cells, B cells, monocytes, natural killer cells, basophils, neutrophils, eosinophils, dendritic cells, fibroblasts, endothelial cells, and vascular endothelial cells, whereas the type II receptor is also expressed on T cells, B cells, and monocytes. Only the type I receptor transduces a signal in response to IL-1;the type II IL-1 receptor, on binding to IL-1, does not. 

Therefore, the type II IL-1 receptor may act as a decoy receptor, preventing IL-1 from binding to the type I IL-1 receptor.IL-1 signal transduction pathways are associated with TNF receptor-associated factor (TRAF) adaptor proteins, particularly TRAF-6 .TRAF-6 associates with IL-1 receptor-associated kinase, which is recruited to and activated by the IL-1 receptor complex .(134,135)

c. ROLE IN ASTHMA
Effects on airways.
IL-1 induces fever, like other endogenous pyrogens such as TNF and IL-6. It causes leukocytosis by release of neutrophils from the bone marrow and induces the production of other cytokines, including IL-6. 

IL-1  is a growth factor for mature and immature thymocytes and a cofactor in the induction of proliferation of and IL-2 secretion by peripheral blood CD4+ and CD8+ T cells after engagement of their antigen receptors.IL-1 also functions as a growth factor for B cells .IL-1 induces many other cytokines, such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, RANTES, GM-CSF,IFN- ,PDGF, and TNF, in a variety of cells. IL-1 induces fibroblasts to proliferate ,an effect that may be the result of release of PDGF ,it increases PG synthesis and collagenase secretion ,and it increases the synthesis of fibronectin and types I, III, and IV collagen IL-1 together with TNF-  and IFN-  can induce or up-regulate the expression of ICAM-1 and VCAM(vascular cell adhesion molecule )-1 on endothelial cells and on respiratory epithelial cells, which may lead to increased adhesion of eosinophils to the vascular endothelium and respiratory epithelium.(136,137,138)

2. Tumor necrosis factor-

a. SYNTHESIS AND RELEASE
Two major forms of TNF exist, i.e., TNF-  and TNF- , which have only 35% amino acid homology but bind to similar receptors. TNF-  (previously known as cachectin) is expressed as a type II membrane protein attached by a signal anchor transmembrane domain in the propeptide .TNF-  is released from cells by proteolytic cleavage of the membrane-bound form by a metalloproteinase (TNF-converting enzyme).TNF-   is produced by many cells, including macrophages, T lymphocytes, mast cells, and epithelial cells, but the principal source is macrophages.(139,140)
b. RECEPTORS.
TNF-  interacts with two cell surface receptors, i.e., p55 and p75. Both receptors are members of the nerve growth factor receptor superfamily. They are derived from the extracellular domains of the receptors and may act as inhibitors of TNF effects .TNF receptors are distributed on nearly all cell types except red blood cells and resting T lymphocytes. The p75 receptor is more restricted to hematopoietic cells. p75 is the principal receptor released by human alveolar macrophages and monocytes in the presence of  IFN-  .
Several signaling pathways leading to activation of different transcription factors, such as NF-B and AP(activator protein)-1.The TRAF(tumor necrosis factor receptor-associated factor) family of adaptor proteins, particularly TRAF-2, is involved in signaling from the TNF receptors .TRAF-2 may also play a role in the pathway of signal transduction from the TNF receptors to activation of the MAP kinase cascade. TNF activates a sphingomyelinase, resulting in the release of ceramide from sphingomyelin, which in turn activates a Mg2+-dependent protein kinase.(141,142)

c. ROLE IN ASTHMA.
Effects on airways.
TNF-  potently stimulates airway epithelial cells to produce cytokines, including RANTES, IL-8, and GM-CSFand it increases the expression of ICAM-1 .TNF-  also has synergistic effects with IL-4 and IFN-  to increase VCAM-1 expression on endothelial cells. TNF-  enhances the expression of class II MHC(major histocompatibility complex)molecules on antigen-presenting cells. In addition, it enhances the release of IL-1 by these cells. It acts as a co-stimulatory factor for activated T lymphocytes, enhancing proliferation and expression of IL-2 receptors. TNF-  also inhibits bone resorption and synthesis and induces proliferation of fibroblasts. TNF-  stimulates bronchial epithelial cells to produce tenascin, an extracellular matrix glycoprotein. (143,144,145)

3. Interleukin-6.

a. SYNTHESIS AND RELEASE
It is secreted by monocytes/macrophages, T cells, B cells, fibroblasts, bone marrow stromal cells, keratinocytes, and endothelial cells. Epithelial cells also appear to produce IL-6 .Human airway smooth muscle cells, upon activation with IL-1  or TGF- , can release IL-6 .Major basic protein secreted from eosinophils can interact with IL-1  or TGF-  to increase IL-6 release from fibroblasts .(146,147)

b. RECEPTORS
High affinity IL-6 receptors are formed by the association of the IL-6 receptor  -chain (which binds IL-6 with low affinity) with   -chain (gp130) (which does not bind IL-6 but associates with the  -chain/IL-6 complex and is responsible for signal transduction) .(148)

c. ROLE IN ASTHMA.
Effects on airways.
IL-6 is a pleiotropic cytokine whose role in asthma remains unclear. IL-6 has growth-regulatory effects on many cells and is involved in T cell activation, growth, and differentiation. It is a terminal differentiation factor for B cells and induces Ig (IgG, IgA, and IgM) secretion. IL-6 is an important cofactor in IL-4-dependent IgE synthesis.IL-6 may also have anti-inflammatory effects. IL-6 can inhibit the expression and release of IL-1 and TNF from macrophages.(149,150)

4. Interleukin-11.
a. SYNTHESIS AND RELEASE
IL-11, which is distantly related to IL-6, is produced by fibroblasts and human airway smooth muscle cells when they are stimulated by IL-1 and TGF- 1.(151)
b. RECEPTORS.
A single class of specific receptors: Like IL-6, IL-11 uses the IL-6 signal transducer gp130. Upon ligand binding, phosphorylation of tyrosine residues in several proteins occurs.(152)
c. ROLE IN ASTHMA
Effects on airways.
IL-11 induces the synthesis of the tissue inhibitor of metalloproteinase-1. It inhibits IL-12 and TNF-  production from monocytes/macrophages effects mediated at the transcriptional level by inhibition of NF- B. (153) 

5. Granulocyte-macrophage colony-stimulating factor.

a. SYNTHESIS AND RELEASE.
GM-CSF is one of the colony-stimulating factors that act to regulate the growth, differentiation, and activation of hematopoietic cells of multiple lineages. GM-CSF is produced by several airway cells, including macrophages, eosinophils, T lymphocytes, fibroblasts, endothelial cells, airway smooth muscle cells, and epithelial cells.
b. RECEPTORS.
The GM-CSF receptor consists of a low affinity  -chain and  -chain that is shared with the IL-3 and IL-5 receptor  –chain. These receptors are usually distributed on granulocytes, monocytes, endothelial cells, and fibroblasts.(154) 
c. ROLE IN ASTHMA.
Effects on airways.
GM-CSF is a pleiotropic cytokine that can stimulate the proliferation, maturation, and function of hematopoietic cells. GM-CSF may be involved in priming inflammatory cells, such as neutrophils and eosinophils. It can prolong the survival of eosinophils in culture.GM-CSF can enhance the release of superoxide anions and cys-LTs from eosinophils .GM-CSF can also induce the synthesis and release of several cytokines, including IL-1 and TNF -, from monocytes. GM-CSF induces nonhematopoietic cells, such as endothelial cells, to migrate and proliferate.(155)

6. Stem cell factor. (SCF)

a. SYNTHESIS AND RELEASE.
SCF (previously known as c-Kit ligand) is produced by bone marrow stromal cells, fibroblasts (including bronchial subepithelial myofibroblasts and nasal polyp fibroblasts), and epithelial cells, such as nasal polyp epithelial cell.(156,157)
b. RECEPTORS.
The receptor for SCF is c-Kit, a receptor protein kinase. It is expressed on early hematopoietic progenitor cells and allows a synergistic response to SCF and lineage-committing growth factors (such as GM-CSF for myelocytes). Expression of c-Kit decreases with cell maturation and is absent from mature cells released from the bone marrow. However, c-Kit expression increases on mast cells as they mature, and receptors are abundantly expressed on the surface of mast cells. c-Kit is also expressed on human eosinophils.(158)
c. ROLE IN ASTHMA
Effects on airways.
SCF acts as a survival factor for the early hematopoietic progenitor cells and synergizes with other growth factors to regulate the proliferation and differentiation of cells. SCF is a major growth factor for human mast cells.Two alternative splice variants account for the different forms of SCF; one is primarily membrane bound and the other is primarily soluble, after being released from the cell surface by proteolysis.CD34+ bone marrow cells with recombinant human SCF and IL-3 induce the development of mast cells and other hematopoietic lineages.

Membrane-bound SCF may influence mast cell adhesion,and soluble SCF is chemotactic for mast cells. SCF has a modest capacity for directly activating  mast cells but is usually more active in priming mast cell responses to other stimuli, such as IgE-stimulated mediator release.SCF causes the release of small amounts of IL-4 and TNF-  from human lung mast cells.(160,161)

D. Inhibitory Cytokines 

1. Interleukin-10.

a. SYNTHESIS AND RELEASE
In humans, Th0, Th1, and Th2-like CD4+ T cell, cytotoxic T cells, activated monocytes, and peripheral blood T cells, including CD4+ and CD8+ T cells, have the capacity to produce IL-10. Mast cells also have the capacity to produce IL-10. Constitutive IL-10 secretion occurs in healthy lungs, with the major source being alveolar macrophages; however, circulating monocytes appear to be able to secrete more IL-10 than alveolar macrophages.(162)
b. RECEPTORS. 
The IL-10 receptor is a member of the class II subgroup of cytokine receptors (the IFN receptor family). The IL-10 receptor has been characterized and cloned from a human lymphoma cell line;it is expressed in several lymphoid and myeloid cell types and in natural killer cells. The IL-10 receptor is highly effective in recruiting the signaling pathways of IL-6-type cytokine receptors, including signal transduction-activated transcription factors 1 and 3 .The inhibitory effects of IL-10 on monocytes appear to be dependent on NF -B.(163)
c. ROLE IN ASTHMA
Effects on airways. 
IL-10 is a potent inhibitor of monocyte/macrophage function, suppressing the production of several proinflammatory cytokines, including TNF- , IL-1 IL-6, MIP  -1, and IL-8,although the release of MCP-1 is increased .IL-10 inhibits monocyte MHC class II, B7.1/B7.2, and CD23 expression and accessory cell function. Accessory signals mediated by B7 molecules through CD28 on the surface of T cells are essential for T cell activation.

Expression of IL-10 up-regulates the monocyte expression of IL-1ra, another anti-inflammatory cytokine.IL-10 suppresses the synthesis of superoxide anions and NO by activated monocytes/macrophages. An anti-IL-10 antibody enhances the release of cytokines from activated monocytes, suggesting that this cytokine may play an inhibitory role when the cell is stimulated. IL-10 inhibits the stimulated release of RANTES and IL-8 from human airway smooth muscle cells.(164,165)


2.Interleukin-1 receptor antagonist. 
IL-1ra shares 26 and 19% amino acid homology with IL-1  and IL-1,  , respectively. It binds to the IL-1 receptor with affinity similar to that IL-1  or IL-1  ,and it inhibits most effects of IL-1 on cells, such as thymocyte proliferation, IL-2 synthesis by T cells, and PGE2 and collagenase production by fibroblasts .IL-1ra is preferentially produced by alveolar macrophages.IL-1ra blocks proliferation of Th2. (166,167)

3. Interferon- .

a. SYNTHESIS AND RELEASE.
IFN-  was originally identified as a product of mitogen-stimulated T lymphocytes that inhibited viral replication in fibroblasts. The only known sources of IFN are CD4+ and CD8+ T cells and natural killer cells.
b. RECEPTORS.
The IFN-  receptor is a single transmembrane protein, a member of thecytokine receptor type II superfamily. Although the receptor binds IFN-  with high affinity, signal transduction requires a species-specific accessory protein that associates with the extracellular domain of the receptor. The receptor is expressed on T cells, B cells, monocytes/macrophages, dendritic cells, granulocytes, and platelets. Epithelial and endothelial cells also express these receptors.
c. ROLE IN ASTHMA
Effects on airways. 
IFN  -is produced by Th1 cells and exerts an inhibitory effect on Th2 cells. IFN-  a increases the production of IL-1, PAF, and hydrogen peroxide in monocytes, in addition to down-regulating IL-8 mRNA expression, which is up-regulated by IL-2 .IFN-  also synergizes with the effects of TNF-  on the production of RANTES from airway smooth muscle cells .On the other hand, IFN-  inhibits IL-10 production from monocytes which leads to an up-regulation of TNF-  transcription .Thus, IFN-  promotes cell-mediated cytotoxic responses while inhibiting allergic inflammation and IgE synthesis. (168,169)

4. Interleukin-12.
a.SYNTHESIS AND RELEASE.
IL-12 was recognized as a cytokine capable of synergizing with IL-2 to increase cytotoxic T lymphocyte responses, as well as an inducer of IFN-  synthesis by resting human peripheral blood mononuclear cells. IL-12 is secreted by antigen-presenting cells, including B lymphocytes and monocytes/macrophages .(170)
b. RECEPTORS. 
IL-12 receptors are expressed on T cells and natural killer cells. One component of the IL-12 receptor complex is related to gp130.The expression of the IL-12 receptor  2-subunit under the influence of IFN-  determines the responsiveness of Th1 cells to IL-12.(171,172)
c. ROLE IN ASTHMA.
Effects on airways
IL-12 enhances the growth of activated T cells and natural killer cells and enhances cytotoxic T cell and natural killer cell activity . IL-12 stimulates natural killer cells and T cells to produce IFN- , promotes differentiation of human T cells that secrete IFN-  and TNF-  ,and inhibits the differentiation of T cells into IL-4-secreting cells .IL-12 indirectly inhibits IL-4-induced human IgE responses by IFN-  dependent and independent mechanisms. (173,174) 

5. Interleukin-18. 
IL-18 (IFN--inducing factor) is a cytokine that is a potent inducer of IFN-  production and plays an important role in Th1 responses.IL-18 is synthesized as a precursor molecule without a signal peptide and requires the IL-1-converting enzyme (caspase-1) for cleavage into a mature peptide.IL-18 induces IL-8, MIP-1, and MCP-1 expression in human peripheral blood mononuclear cells in the absence of any co-stimuli. IL-18 directly stimulates gene expression and synthesis of TNF-  in CD3+/CD4+ T cells and natural killer cells, with subsequent production of IL-1 and IL-8 in CD14+ monocytes.(175,176)

E.Growth Factors
1. Platelet-derived growth factor.
a. SYNTHESIS AND RELEASE. 
PDGF(platelet-derived growth factor) is released from many different cells in the airways and consists of two peptide chains, so that AA, BB, or AB dimers may be secreted by different cells. PDGF-A and -B chains are both synthesized as HMW precursors, which are then extensively processed before secretion.Posttranslational glycosylation and proteolytic cleavageboth contribute to the heterogeneity in the apparent molecular weights of the mature proteins. Most of the PDGF present in human platelets.The sources of PDGF include platelets, macrophages, endothelial cells, fibroblasts, airway epithelial cells, and vascular smooth muscle cells. Various stimuli, such as IFN-  for alveolar macrophages, hypoxia, basic FGF (bFGF- fibroblast growth factor), and mechanical stress for endothelial cells, and serum.TNF- , IL-1, and TGF-  for fibroblasts, can induce PDGF release.(177,178)
b. RECEPTORS. 
Two classes of PDGF receptors,  These are single-transmembrane domain glycoproteins with an intracellular tyrosine kinase domain .Binding of PDGF dimers induces receptor dimerization, with three possible configurations .The PDGF receptor  -subunit binds both PDGF A- and B-chains, whereas the receptor  -subunit binds only PDGF B-chains. Therefore, PDGF-AA binds only to PDGF    receptor dimers, PDGF-AB to    receptor and    dimers, and PDGF-BB to all three configurations (  ,  ,  ) .These receptors are widely distributed on cells of mesenchymal origin, including fibroblasts and smooth muscle cells.(179,180)

c. ROLE IN ASTHMA.
Effects on airways.. 
PDGF is a major mitogen, with its primary regulatory role being directed at the cell cycle; it acts as a competence factor, triggering early events of the cell cycle that lead to DNA synthesis and mitosis. PDGF may activate fibroblasts to proliferate and secrete collagen ,and it may also stimulate proliferation of airway smooth muscle ,which is mediated by the receptor .PDGF can be a chemoattractant for connective tissue cells and can stimulate fibroblasts to contract collagen lattices.(181,182)

2. Transforming growth factor-.
a. SYNTHESIS AND RELEASE.
Monocytes constitutively express TGF- 1 mRNA. Lung fibroblasts themselves may be a source of TGF-  ,but TGF-  is also secreted by inflammatory cells, including eosinophils neutrophils and airway smooth muscle cells, and structural cells, such as epithelial cells . (183)
b. RECEPTORS
The TGF-   receptor exists in three forms, i.e., high affinity types I and II and low affinity type III .The high affinity receptors are serine/threonine kinases related to the activin receptor and are thought to associate to mediate signal transduction, probably through serine/threonine phosphorylation. The type II receptor includes   -glycan and endoglin in its structure and does not transduce signals, but it may concentrate TGF-  on the cell surface and present the ligand to the other receptors.(184) 
c. ROLE IN ASTHMA.
Effects on airways.
TGF-  They may either inhibit or stimulate proliferation of fibroblasts, depending on the presence of other cytokines. TGF-  induces the transcription of fibronectin, which can function as a chemotactic agent and growth factor for human fibroblasts. TGF- may also be involved in the process of repair of the airway epithelial damage that is characteristic of asthma, because TGF-  is a potent inducer of differentiation for normal epithelial cells. TGF-  is a potent profibrotic cytokine that stimulates fibroblasts to promote the synthesis and secretion of many proteins of the extracellular matrix .TGF-  is also a potent chemoattractant for many cell types, including monocytes, fibroblasts, and mast .TGF-  activates monocytes to produce other cytokines, such as TNF- , TGF- ,TGF- , PDGF- , and IL-1. TGF-  has complex actions in the immune system..(185,186,187)

3. Fibroblast growth factor.
FGF represents a family of heparin-binding growth factors consisting of seven polypeptides, including acidic FGF and bFGF. Acidic FGF and bFGF are potent modulators of cell proliferation, motility, and differentiation. They are found to be associated with the extracellular matrix. bFGF induces an invasive phenotype in cultured endothelial cells, enabling them to penetrate the basement membrane bFGF induces increased production of proteolytic enzymes, plasminogen activators, and collagenase. bFGF binds to heparan sulfate proteoglycans in basement membranes.In human adult lung, bFGF has been localized to vascular smooth muscle and endothelial cells of blood vessels of the lungs . bFGF increases expression of the PDGF receptor  -subunit in human airway smooth muscle and therefore indirectly stimulates proliferation.(188,189)

4. Epidermal growth factor. 
EGF and TGF- , which do not bind heparin, but stimulate angiogenesis. EGF increases airway smooth muscle proliferation ,and ET-1 potentiates EGF-induced airway smooth muscle proliferation ,Increases in the number of blood vessels in asthmatic airways.(190)

5. Insulin-like growth factor. 
IGF is produced by airway epithelial cells & is a potent mitogen for airway smooth muscle proliferation. IGF appears to mediate the proliferative effect of LTD4 on airway smooth muscle.(191,192) 

CHEMOKINES
The CC chemokines are involved in chemoattraction of eosinophils, monocytes, and T lymphocytes.A third chemokine family (C chemokines), with a single cysteine residue (of which lymphotactin is the first example), and a fourth family (CXXXC family), with three residues separating the two cysteine residues (of which fractaline is an example).
A. CC Chemokines 
1. SYNTHESIS & METABOLISM.
In general, monocytes and tissue macrophages are rich sources of CC chemokines, usually associated with de novo synthesis. MCP-1 and MCP-2 are major stimulated products of monocytes. Lymphocytes are sources of some CC chemokines, particularly RANTES ,I-309 MIP-1,and MIP-1.Neutrophils can produce MIP-1.RANTES and eotaxin are also produced by cultured human airway smooth muscle cells .MCP-1 and RANTES are produced by human eosinophils (193,194)
2. RECEPTORS. 
The chemokine receptors form a family of structurally and functionally related proteins that are members of the superfamily of G protein-coupled receptors. The known receptors include CCR1, which binds MIP-1 , RANTES, and MCP-3 ,CCR(chemokine receptor)2, which binds MCP-1 and MCP-3,CCR3, which binds eotaxin, RANTES, MCP-3, and MCP-4, CCR4, which binds MCP-1, MIP-1, and RANTES .and CCR5, which binds MIP-1, MIP-1, and RANTES . (195,,196,197)
3. ROLE IN ASTHMA.
Effects on airways. 
MIP-1 that bind to proteoglycans binds to endothelium to trigger the adhesion of T cells (particularly CD8+ T cells) to VCAM-1 .MIP-1 has been localized to lymph node endothelium and could act as a tethered ligand on endothelial cells, thus providing the required signals for activation of lymphocyte integrins for adhesion to endothelium and for migration.
RANTES(regulated on activation normal T cell-expressed and secreted protein)is a chemoattractant for memory T cells. Human MIP(macrophage inflammatory protein)-1  and -  are also chemoattractants for distinct subpopulations of lymphocytes, i.e., MIP-1 for CD8+ and MIP-1  for CD4+ T lymphocytes.RANTES attracts both phenotypes and acts on resting and activated T lymphocytes, whereas MIP-1 and MIP-1 are effective only on anti-CD3-stimulated cells . In the presence of IL-3, IL-5 or GM-CSF, there is enhanced release of histamine and production of LTC4.RANTES is the most effective basophil chemoattractant, whereas MCP-1 is more effective as an inducer of histamine and LT release.Eotaxin-1 and eotaxin-2 also are chemoattractant for basophils,in addition to stimulating release of histamine and LTC4 .(198,199,200)
B. CXC Chemokines 
1.SYNTHESIS & METABOLISM
Platelet factor-4, stored in platelet granules, was the first member of the CXC chemokine family. However, IL-8 [also referred to as neutrophil-activating protein (NAP)-1], with its major actions being as a neutrophil chemoattractant and activator. Several other CXC chemokines that are similar to IL-8 were including NAP-2 (arising from amino-terminal processing of platelet basic protein) ,growth-related oncogene protein (GRO)- , GRO- , and GRO-  epithelial cell-derived neutrophil-activating protein and granulocyte chemotacticprotein-2.Asecreted protein produced by lipopolysaccharide-stimulated murine macrophages, termed MIP-2, was found to be a chemoattractant for human neutrophils and to be closely related to GRO(growth-related oncogene).In general, monocytes and tissue macrophages are rich sources of CXC chemokines, usually associated with de novo synthesis.(201,202,203)

2. RECEPTORS.
Two receptors for IL-8 one of high affinity (IL-8 receptor type 1) and the other of low affinity(IL-8 receptor type 2).These receptors form a family of structurally and functionally related proteins, being members of the superfamily of heptahelical, rhodopsin-like G protein-coupled receptors.IL-8 also induces G protein activation in neutrophils .IL-8 receptor type 1 is specific for IL-8.Glu-Leu-Arg in the amino-terminal domain, including IL-8,the GROs, and NEP(neutral endo peptidase)-2, but not by CC chemokines. Neutrophils, basophils, and lymphocytes have been shown to possess functional receptors.(204,205)

3. ROLE IN ASTHMA
Effects on airways.
IL-8 is mainly a neutrophil chemoattractant and activator.IL-8 induces shape changes, transient increases in [Ca2+]i, exocytosis (with release of enzymes and proteins from intracellular storage organelles), and respiratory bursts through activation of NADPH oxidase. IL-8 activates neutrophil 5-LO, with the formation of LTB4 and 5-HETE(hydro eicosa tetraenoic acid) and also induces the production of PAF. IL-8 can also induce [Ca2+] i elevations, shape changes, and release of eosinophil peroxidase in eosinophils from patients with hypereosinophilic syndrome.(206,207) 

PROTEASE
a. SYNTHESIS & METABOLISM. 
Tryptase is a trypsin-like serine protease that is the major component of mast cell granules, particularly in mucosal mast cells.Tryptase is associated with heparin in mast cell granules and is secreted by exocytosis. Tryptase is secreted as a glycosylated heparin-bound tetramer. Chymase and the related protease cathepsin G are found in the connective tissue type of mast cells and are bound to heparin in mast cell granules. Both have chymotrypsin-like activity. Several MMPs comprise a group of structurally related proteases that are secreted by inflammatory and structural cells. MMP-9 (gelatinase B) is expressed in eosinophils of asthmatic airways .Neutrophil elastase, which is a serine protease derived from neutrophils, may also be involved in asthma.(208)
b. RECEPTORS. 
MMPs(matrix metalloproteinase)and neutrophil elastase produce their effects through degradation of matrix proteins, including collagen, elastin, and fibronectin. Tryptase and chymase cleave  specific proteins. 
Chymase also degrades matrix proteins and may activate MMPs by cleaving the active enzyme from an inactive precursor peptide. Some of the effects of tryptase and chymase appear to be mediated by protein-activated receptors that are similar to the thrombin receptor. Tryptase activates protein-activated receptor-2 by cleaving part of the amino-terminal extracellular domain; this reveals sequences that then activate the G protein-coupled receptor, leading to signal transduction.(209,210)
ROLE IN ASTHMA
Effects on airways
AIRWAY SMOOTH MUSCLE.
Tryptase increases the responsiveness of human airways to histamine and this effect is more pronounced in sensitized airways.Tryptase may also increase bronchoconstriction by degrading bronchodilating neuropeptides-VIP(vasoactive intestinal polypeptide) and peptide histidine.Typtase also potently degrades CGRP(calcitonin gene related peptide). Tryptase is a potent stimulant of airway smooth muscle proliferation. (211,212,213)
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