the healthy balance of normal processes in the lungs , termed pulmonary homeostasis , can be disturbed by external environmental insults or endogenous factors produced during other diseases . in response to insults , the lung responds with an ancient protective mechanism , inflammation . the subsequent course of events depends on the severity of the injury and on the effectiveness of the inflammatory response ( figure 1 ) . if the injury is mild , structural damage to the lung is limited and the lung tissue will rapidly return to homeostasis ( figure 1a ) . if the injury is more profound and the structural integrity of the tissue and/or vitality of cells are impaired , then the defect in the tissue will be  patched  with newly formed connective tissue  scar . this repair process substitutes functional components of the tissue with extracellular matrix , which fills the defect and , in most cases , allows for the return to tissue homeostasis ( figure 1b ) . however , problems arise when the injury is severe or repetitive , and the inflammatory and repair processes fail to limit themselves . under these circumstances , chronic inflammation and exaggerated repair can ensue , in some cases leading to excessive accumulation of extracellular matrix , or so - called pulmonary fibrosis ( figure 1c ) . in this brief report , we present the regulation of these processes by key cytokines in three representative chronic diseases of the lung  asthma , copd , and pulmonary fibrosis . ( a ) if the injury is mild and structural damage to the tissue is minimal , the process of regeneration allows for a rapid return to homeostasis . ( b ) a more profound injury affecting the structural integrity of the tissue and vitality of cells leads to repair with deposition of scar tissue , but in most cases there is a return to homeostasis . ( c ) repetitive injury , primary or secondary , combined with disturbed tissue responses may lead to continuous inflammation and exaggerated repair , resulting in fibrosis . note the central involvement of inflammation in all cases , as a bridge between the immediate response to injury and the subsequent repair processes . although there is a certain overall directionality of the sequence of events from injury to inflammation and to repair , these processes often occur simultaneously at a given time , as indicated by the overlapping corresponding curves . cytokines participate in cell - cell communication and regulate many functions including cell survival , cell growth , and induction of gene expression . cytokines can be produced by many cell types . during the adaptive immune response , cd4 +  helper t - cells these helper cells can become th1 cells making high levels of interferon ( ifn) , th2 cells making high levels of interleukin ( il)-4 , il-5 , and il-13 , or th17 cells making high levels of il-17 . while each disease has unique attributes , several cytokines play roles in all three diseases and , thus , may provide interesting targets for therapeutic intervention . asthma is a chronic disease of the lung characterized by shortness of breath , wheeze , cough , reduced airflow on expiration , and airway hyperreactivity to non - specific bronchoconstrictors . recent evidence suggests that asthma is not a single disease , but consists of several subtypes , including allergic and steroid - resistant asthma . allergic asthma is mediated by the th2 cytokines il-4 , il-5 , and il-13 ( table 1 ) . il-4 participates in the differentiation of nave cd4 + t cells into the th2 type and is important for the production of allergen - specific ige . furthermore , il-4 drives the alternative activation of macrophages , which have been shown to increase lung inflammation in mouse models of allergic lung inflammation and to be correlated with asthma severity in asthma patients [ 6 - 12 ] . the role of il-4 in driving allergic asthma is well known , and recent data suggest that its alternatively spliced variant missing exon 2-encoded region , il-42 , is naturally produced by cells from patients with asthma but not from healthy controls . this splice variant is active independently of wild - type il-4 and promotes pulmonary inflammation without th2 skewing . the relative importance of these cytokines is difficult to assess quantitatively ; instead , the authors established this order based on their expertise and available literature in the field . abbreviations : ccl17 , thymus and activation - regulated chemokine ( also known as tarc ) ; copd , chronic , obstructive pulmonary disease ; ctgf , connective tissue growth factor ; gm - csf , granulocyte - macrophage colony - stimulating factor ; il , interleukin ; mcp-1 , monocyte chemotactic protein ( also known as ccl2 ) ; parc , pulmonary and activation - regulated chemokine ( also known as ccl18 ) ; pdgf , platelet - derived growth factor ; rantes , regulated and normal t cell expressed and secreted ; sdf-1/cxcl12 , stromal cell - derived factor-1 ; tgf- , transforming growth factor beta ; tnf- , tumor necrosis factor alpha ; tslp , thymic stromal lymphopoietin ; vegf , vascular endothelial growth factor . like il-4 , il-13 can also regulate ige production and the alternative activation of macrophages because it shares a receptor complex and downstream signaling pathways with il-4 . furthermore , il-13 has a distinct and prominent role in mediating the structural changes observed in the airways by modulating goblet cell differentiation and mucus production , airway smooth muscle cell proliferation , and subepithelial fibrosis . such changes lead to airway constriction and hyppereactivity to stimulants , and , after prolonged chronic allergen exposure , tissue remodeling and fibrosis . studies in both mouse models and human asthmatics have demonstrated that il-5 is critical for the differentiation of eosinophils from bone marrow precursors and for their trafficking from the bone - marrow to the lung [ 19 - 24 ] . thus , the th2 cytokines il-4 , il-13 , and il-5 orchestrate the set of physiological responses characteristic of allergic asthma including inflammation , airway hyperactivity , and airway remodeling . in addition to the classic th2-cell derived cytokines , cytokines produced by airway epithelial cells have recently been recognized as critical mediators of allergic asthma . airway epithelial cells are the first to encounter inhaled allergens or other agents and are stimulated to secrete il-25 , il-33 , and thymic stromal lymphopoietin ( tslp ) [ 30 - 33 ] . il-25 is produced by airway epithelial cells upon exposure to allergens , particles , and helminths . il-33 is present in cells in both full - length and mature forms , of which mature il-33 is a powerful activator of the th2 responses [ 29,36 - 41 ] , whereas full length il-33 activates inflammation without engaging the il-33 receptor component t1/st2 or engaging the th2 mechanisms . both il-25 and il-33 stimulate the rapid production of il-5 and il-13 by natural helper cells ( multipotent progenitor cells , nuocytes , c - kit+sca-1+il-7r+ il-33r+il-17rb+ cells ) in the airways , which promotes th2 generation and increases local th2 cytokine production [ 45 - 49 ] . tslp primes , polarizes , and maintains th2 cells , and its expression in the airways of patients with asthma has been shown to correlate with disease severity [ 51 - 53 ] . all these th2-associated cytokines are engaged in an intricate interplay with other cytokines including , but not limited to , tnf- [ 54 - 56 ] , il-1 , granulocyte - macrophage colony - stimulating factor ( gm - csf ) , vascular endothelial growth factor ( vegf ) [ 61 - 64 ] , il-18 [ 65 
 66 ] , and il-17 [ 67 - 73 ] . based on studies in mouse models , it is believed that th17 cells and , therefore , il-17 cytokines play a role in asthma severity by increasing neutrophil recruitment to the airways . furthermore , the th17-mediated pathway may contribute to steroid resistance in human asthma , but this has not yet been clearly established . thus , il-17-driven asthma may be distinct from allergic asthma and require different therapeutic strategies . the chemotactic family of cytokines called chemokines also centrally contributes to pathogenesis of asthma by recruiting specific inflammatory cells into the lung tissue [ 75 - 77 ] , including regulated and normal t cell expressed and secreted ( rantes)/ chemokine ( c - c motif ) ligand ( ccl)5 [ 78 - 81 ] , eotaxins ccl11 , ccl24 , and ccl26 [ 81 - 84 ] , cxcl8/il-8 . while the th1 cytokine ifn- is typically thought to suppress th2-mediated responses , several reports indicate that , in certain circumstances , ifn- is also involved in promoting disease pathogenesis [ 87 - 89 ] . copd is caused by smoking or other prolonged significant exposure to fumes , dust , or polluted air , which causes chronic inflammation of bronchi , destruction of lung tissue ( emphysema ) , and some degree of scarring . the inflammatory process involving t cells , neutrophils , and macrophages is driven by the classical proinflammatory cytokines tnf- , ifn- [ 92 - 94 ] , il-1 , il-6 , il-8 [ 90,91,97 - 102 ] , il-18 , and il-32 . recent evidence also implicates il-17 in the pathogenesis of copd [ 56,92,106 - 109 ] . increased sputum il-17 levels were identified in copd patients , and were even more pronounced than those detected in patients with asthma . these levels correlated with a decrease in lung function as measured by a decrease in forced expiratory volume , suggesting a potential role for il-17 in copd pathogenesis and defining it as a prognostic target for disease immunotherapy . although copd is not considered a th2 disease , activated th1 and th2 cells are found in copd patients , suggesting that both may contribute to the disease processes . for example , the pro - th2 cytokine tslp is expressed and functionally active not only in patients with asthma but also in patients with copd . similarly , il-13 may be contributing to mucus metaplasia , airway fibrosis , and vascular remodeling in copd . expression of the profibrotic cytokine transforming growth factor ( tgf)- is enhanced in the airways of patients with copd [ 110 - 113 ] . this appears somewhat counterintuitive because tgf- is a potent inducer of connective tissue deposition , whereas copd is characterized predominantly by lung tissue destruction . nevertheless , pulmonary fibroblasts from these patients respond to stimulation by tgf- with an enhanced activation of the wnt/-catenin pathway , whereas copd airway smooth muscles respond to similar stimulation with an enhanced deposition of the proteoglycan perlecan , suggesting that tgf- contributes to architectural changes in the lungs in copd . indeed , peribronchial fibrosis does develop in the lungs of patients with copd , which is in contrast to mostly subepithelial fibrosis in asthma ( see above ) and interstitial fibrosis in idiopathic pulmonary fibrosis and scleroderma lung disease ( see below ) . this process may be self - limiting , but in some cases , the fibrotic process becomes overt and irreversible , leading to a significant decline in lung function , the ability to exchange gas . pulmonary fibrosis is the main cause of death in the autoimmune disease scleroderma , whereas in patients with idiopathic pulmonary fibrosis , median survival is only two to three years . in cases of such profound pulmonary fibrosis , the available therapies have limited effectiveness . extracellular matrix , including collagen , accumulates in the lungs through several mechanisms . resident pulmonary fibroblasts become activated , increase their proliferation rate , while decreasing sensitivity to apoptotic signals , and deposit more extracellular matrix , while slowing down extracellular matrix turnover . bone marrow - derived cells called fibrocytes home to the lung and differentiate into activated fibroblasts [ 118 - 120 ] . epithelial - mesenchymal transition , a process by which lung epithelial cells transform into myofibroblasts , also contributes to lung fibrosis [ 121 - 123 ] . all these mechanisms are controlled by cytokines , either through direct recruitment and activation of extracellular matrix - producing cells , or indirectly , through regulation of pulmonary inflammation [ 124 - 130 ] , redox balance [ 131 - 133 ] , and activity of several enzymatic systems , including matrix metalloproteinases and their inhibitors [ 130,134 - 136 ] , and clotting enzymes [ 126,137 - 141 ] . it is produced in latent form and normally stored as such in tissues in association with extracellular matrix and needs to be activated to exert its functional effect . thus , tgf--driven fibrosis is controlled by the mechanisms of its activation rather than production . in the lungs , activation of tgf- by v - containing integrins plays a central role in the mechanism of fibrosis [ 127,143 - 146 ] . connective tissue growth factor ( ctgf ) acts in concert with tgf- , contributing to fibrosis . furthermore , the th2 cytokines il-4 and il-13 are direct activators of fibrosis [ 149 - 154 ] , whereas the th1 cytokine ifn- is a potent direct inhibitor of extracellular matrix deposition . interestingly , although the levels of th2 cytokines are substantially higher in asthma than in fibrotic diseases such as scleroderma or idiopathic pulmonary fibrosis , the severity of fibrosis is higher in the latter diseases . furthermore , scleroderma lung disease and idiopathic pulmonary fibrosis are characterized by diffuse parenchymal accumulation of extracellular matrix , whereas in asthma , fibrosis is mostly subepithelial . a possible explanation for this paradox is that , in asthma , th2 cytokines are the predominant drivers of fibrosis , whereas in scleroderma lung disease and idiopathic pulmonary fibrosis , the patients experience a  profibrotic cytokine storm  , with elevated levels of all of the cytokines listed in this section . furthermore , tgf- is a more potent profibrotic cytokine , exerting its effect at much lower concentrations than il-4 or il-13 . the chemokine monocyte chemotactic protein ( mcp)-1/ccl2 promotes fibrosis through direct and indirect mechanisms [ 157 - 160 ] , as do oncostatin m   and platelet derived growth factor ( pdgf ) [ 162 - 164 ] . an important , predominantly indirect , modulator of fibrosis is the chemokine pulmonary and activation - regulated chemokine ( parc)/ccl18 , which is elevated in association with various fibrotic lung diseases , such as scleroderma , hypersensitivity pneumonitis and idiopathic pulmonary fibrosis , asthma , and sarcoidosis . although parc / ccl18 directly activates collagen production in fibroblasts in cell culture [ 170 - 173 ] , it exerts its profibrotic action in vivo mostly by recruiting profibrotic t cells . another chemokine , stromal cell - derived factor ( sdf)-1/ chemokine ( c - x - c motif ) ligand ( cxcl)12 , contributes to fibrosis by recruiting bone marrow - derived progenitors of fibroblasts to the lung [ 175 - 177 ] . numerous other cytokines may contribute to the mechanism of pulmonary fibrosis , but their exact roles remain either controversial or mechanistically unclear , including il-1 and il-17 [ 178 - 180 ] , il-10 , thymus and activation - regulated chemokine ( ccl17 ) , and gm - csf [ 184 - 186 ] . an extensive discussion of cytokines regulating pulmonary fibrosis can be found in [ 129,187 - 189 ] . the important contribution of cytokines to features of the chronic lung diseases presented above suggests potential targets for therapeutic intervention using blocking antibodies or therapeutic proteins . indeed , a number of clinical trials have been performed or are ongoing for many of the cytokine targets . the emerging anti - cytokine therapies for asthma are primarily directed toward il-4 , il-5 , or il-13 [ 190 - 195 ] . early studies targeting il-4 met with limited success , likely because they did not also block il-13 . more recent studies with blocking anti - il-13 antibodies or with an il-4 mutant that blocks the actions of both il-4 and il-13 showed greater promise in some , but not all , studies [ 191 - 193,195 - 197 ] . the varied effectiveness of il-13-directed therapies is not surprising considering that only 50% of asthmatics show elevated levels of sputum il-13 . similarly , there are controversial results on the effectiveness of il-5 directed therapies [ 196 , 197 ] . while anti - il-5 antibody was effective at reducing eosinophil numbers in blood and sputum , it was substantially less effective at reducing eosinophil numbers in the lung and had a modest impact on lung function . therefore , it is clear that currently existing therapies have to be extended to include downregulation of additional pathways that have been shown to play roles in asthma pathogenesis such as tslp , il-17 , il-25 , il-33 . other more  non - traditional  molecular pathways might also prove to be effective targets . as an example , we recently have shown that neuroimmune semaphorin 4a plays a downregulatory role in experimental asthma severity , in part , by regulation of il-13 . several drugs targeting the tumor necrosis factor ( tnf)- pathway have been developed and used in clinical settings . some of them ( i.e. mouse / human igg1 antibody against tnf- , ifliximab ) were found to be effective in asthma but not in copd [ 202 - 205 ] . a soluble human tnfr2 , etanercept , reduced lung pathophysiology in patients with severe forms of disease . clinical studies of a fully humanized il-1 blocking antibody ( canakinumab ) and anti - il-6r blocking antibody ( tocilizumab ) were reported to be in progress in patients with copd and rheumatoid arthritis , correspondingly , but no final results have been revealed yet . several drugs have been developed to target the vegf pathway , which has been implicated in asthma , such as bevacizumab , vegf - trap , and ptk737   with clinical trials being limited thus far to cancer , ischemia , and age - related macular degeneration . the identification and targeting of a cytokine active in more than one chronic lung disease would clearly be beneficial . there is growing awareness that there are key similarities in the contribution of cytokines and the manifestation of lung pathology among the chronic respiratory diseases . as noted in table 1 , several of the cytokines contribute to multiple chronic disease states ( e.g. tgf- , il-17 , tslp , il-4 , il-13 ) . while we have learned much about the general role of cytokines in these diseases , many questions remain unanswered . what is the relationship between the major chronic respiratory diseases ? are there common targets for intervention ? will it be possible in the future to attenuate or even abrogate the undesired excessive responses by therapeutically targeting cytokines ? experiments in animals have been very promising , but their translation into clinical trials lags behind . one difficulty is that cytokines are functionally pleiotropic and redundant , and , as a result , targeting an individual cytokine may have a less than expected effect ( due to functional substitution by other , functionally similar , cytokines ) or have undesired side effects ( due to pleiotropy ) . another difficulty is that mouse models do not completely mimic the disease in humans [ 210 - 212 ] . it will be important to further understand these issues to increase the likelihood that targeting cytokines will improve the clinical outcome for patients with chronic lung diseases .