Asma y Tono y Inmune 2006

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Airway Smooth Muscle as a Regulator of ImmuneResponses and Bronchomotor Tone

Aili L. Lazaar, MD T , Reynold A. Panettieri, Jr, MD Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Medical Center, BRB II/III, 421 Curie Boulevard,

Philadelphia, PA 19104-6160, USA

Asthma, a chronic disease with a prevalence of 3% to 5% in the United States, affects millions of people worldwide. Complex genetic and environ-mental factors contribute to the development of asthma, which is characterized by reversible airwayobstruction, airway inflammation, and airway smoothmuscle (ASM) cell hyperplasia. The traditional viewthat in asthma ASM is a purely contractile tissueseems to be inadequate. Compelling evidence nowsuggests that ASM plays an important role inregulating bronchomotor tone, in perpetuating airwayinflammation, and in remodeling of the airways. Thisarticle reviews three distinct functions of ASM cells:the process of excitationcontraction coupling, witha particular focus on the role of cytokines in modu-lating calcium responses; the processes of smoothmuscle cell proliferation and migration; and thesynthetic and immunomodulatory function of ASMcells. It also discusses how altered synthetic functioncontributes to airway remodeling.

Airway smooth muscle shortening and airwayhyperresponsiveness

Airway smooth muscle bronchomotor tone and asthma

Smooth muscle cell shortening regulates airwayluminal caliber. Many studies have examined whether

the nonspecific airway hyperresponsiveness (AHR)characterizing asthma can be attributed to increasedASM force generation as a consequence of alteredreceptorligand interactions or altered signal trans-duction pathways. For example, expression of the bradykinin B2 receptor is increased in ASM exposedto interleukin (IL)-1 b, tumor necrosis factor-alpha(TNFa ), or transforming growth factor-beta (TGF b),whereas the bradykinin B1 receptor is increased bytreatment with IL-4 [15] . In contrast, TNF adramatically decreases muscarinic receptor density but enhances acetylcholine-induced hyperresponsive-ness because of altered downstream signal trans-duction pathways [6,7] .

Despite evidence that ASM derived from patientswho have asthma may not exhibit a greater increasein isometric force generation than in nonasthmatic persons, exposure to inflammatory mediators clearlyenhances force generation of normal tissue to con-tractile agonists. Early studies demonstrated that passive sensitization of human ASM with asthmaticserum nonspecifically increases smooth muscle cell

responsiveness [811] . TNFa and IL-1b induce bronchial hyperreactivity in both humans and ani-mals, whereas in vitro cytokines and other mediators,including TNF a , IL-1b, IL-13, IL-5, lysophospha-tidic acid, and phospholipase A 2 also prime ASMto become hyperresponsive to contractile agonists[1216] . Leukotrienes (LTs) are potent bronchocon-strictors in normal and asthmatic persons, and ASMcells express both receptors for the cysteinyl leuko-trienes, LTC 4, LTD 4, and LTE 4 [17,18] . Expression of the CysLT1 receptor is increased by exposure tointerferon (IFN)- g and results in an increase in LTD 4-

0272-5231/06/$ see front matter D 2006 Elsevier Inc. All rights reserved.doi:10.1016/j.ccm.2005.10.003 chestmed.theclinics.com

T Correspondin g author. E-mail address: [email protected] (A.L. Lazaar).

Clin Chest Med 27 (2006) 53 69
http://dx.doi.org/10.1016/j.ccm.2005.10.003http://chestmed.theclinics.com/mailto:[email protected]:[email protected]://chestmed.theclinics.com/http://dx.doi.org/10.1016/j.ccm.2005.10.003mailto:[email protected]


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mediated force generation in cultured ASM cells[19]. Conversely, TNF a , IL-1b, and IL-13, bu t not IL-4, reduce b-adrenergic relaxation responses [20].Together, these studies suggest that proinflam-matory mediators promote airway hyperresponsive-ness by enhancing ASM contraction or alteringASM relaxation.

Modulation of calcium homeostasis in airway smoothmuscle cells

In human ASM cells, contractile agonists bindGq- or G0-protein coupled receptors (GPCR) andactivate phospholipase C. The subsequent hydrolysisof phosphatidylinositol 4,5 bisphosphate into inositoltrisphosphate and diacylglycerol ultimately increases

cytosolic calcium [21]. Because most inflammatoryagents evoke neither a calcium response or nor phosphoinositide (PI) hydrolysis in human ASM, modu-

lation of agonist-induced increases in intracellular calcium (Ca 2 +i ) by extracellular stimuli probablymodulates downstream GPCR signaling. TNF aincreases the expression as well as the activit y of G-proteins in several cell types, including ASM [20].The effect of cytokines on agonist-evoked calciumresponses seems to be stimulus specific, however, because bradykinin-evoked PI accumulation is sig-nificantly enhanced by TNF a and IL-1 b, whereas IL-1b dimin ishes histamine-induced PI metabolism[1,22,23] .

The level of Ca 2 +i , in ASM modulates excitation contraction coupling and force generation ( Fig. 1)[24]. Agonist-induced elevations in Ca 2 +i activatethe calcium-/calmodulin-sensitive myosin light chainkinase (MLCK), leading to phosphorylation of the

regulatory myosin light chain (MLC 20 ). Phosphory-lation of MLC 20 initiates cross-bridge cycling between myosin and actin and sustains ATP binding,

Fig. 1. Cytokine effects on excitation contraction coupling in ASM cells. Cytokines binding to their receptors influenceintracellular signaling as well as the function and expression of GPCRs and CD38. Alterations in intracellular signaling affect calcium homeostasis and calcium sensitization. cADPR, cyclic ADP ribose; CaM, calmodulin; DAG, diacylglycerol; GEF,guanine exchange factor; GPCR, G-proteincoupled receptor; IP3, inositol 3-phosphate; MLC, myosin light chain; MLCK,myosin light chain kinase; PLC, phospholipase C; R, cytokine receptor; RyR, ryanodine receptor; SR, sarcoplasmic reticulum.

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hydrolysis and ADP release. Dephosphorylation bythe MLC phosphatase termin ates cross-bridge cyclingand relaxes smooth muscle [21]. Evidence now sug-gests that abnormalities in these two major regulatoryevents (increases in Ca 2 +i and MLC phosphoryla tion)induce bronchial hyperresponsiveness in asthma [12].

Agonist-evoked calcium responses and calcium sensitization

Calcium homeostasis in cultured ASM cells isaltered by inflammatory mediators. Cytokines such asTNFa , IL-1b, or IL-13 enhance cytosolic calciumresponses in human ASM induced by carbachol, bradykinin, or thrombin [1,15,25] . In contrast, IL-4suppresses carbachol-induced calcium signals [26,27] .Other stimuli may directly enhance agonist-inducedcalcium signaling in cultured ASM cells, includingeosinophil-derived polycationic proteins or major ba-sic protein, the aldehyde pollutant acrolein, or phospholipase A2 [11,28,29] .

More recently, a phenomenon known as calciumsensitization has been described that involves cal-cium-independent mechanisms for maintaining MLC phosphorylation and smooth muscle contraction [30].The signaling pathways for calcium sensitizationinvolve inhibition of MLC phosphatase and, thus,inhibition of MLC dephosphorylation, most notably

by Rho/Rho kinase and integrin-linked kinase [30].Ultimately, enhanced MLC phosphorylation increasesactinmyosin interactions.

Aberrant RhoA/Rho kinase activation has beenimplicated in a variety of disease states [31]. In ASMcells, carbachol- and TNF-induced calcium sensi-tization is mediated through activation of RhoA/ Rho kinase [32,33] . Additionally, animal models of allergen-induced AHR and airway inflammationdemonstrate increased RhoA activation; in turn,antigen-induced AHR is abrogated by pharmacologicinhibition of Rho kinase [34,35] . Allergen sensitiza-tion also increases lung expression of Rho and di-rectly impugns Rho kinase in agonist-induced ASMcontraction [36]. Thus, pathways that modulate Rhoand Rho kinase activation, particularly dysregulatedcontractile responses, may play an important role inasthma pathogenesis.

CD38Recent studies show that CD38, a membrane-

bound protein expressed on ASM cells, modulatescyclic adenosine diphosphate ribose (cADPR) levels[37]. cADPR, a b-nicotinamide adenine dinucleotidemetabolite, contributes to agonist-induced elevationof Ca2 +i concentration in ASM cells by activating

ryanodine receptors [38,39] . Recently, TNF a andIL-13 have been sh own to increase expression of CD38 on ASM cells [40,41] . Furthermore, a cADPR antagon ist inh ibited agonist-induced increases inCa2I

+ [40,42] . Finally, agonist-induced increases inlung resis tance are attenuated in CD38-deficient ani-mals [43], suggesting that CD38 expression on ASM plays a significant role in maintaining calciumhomeostasis and contributes to AHR.

Alterations in the biophysical properties of airway smooth muscle can modulate airway smooth muscle shortening

Proinflammatory mediators may also alter theinternal resistance to shortening of the muscle,thereby affecting force generation. For example,MLCK content is increased in sensitized airways[44], which may contribute to the enhanced short-ening velocity of ASM from asthmatic patients [45] .Alternatively, TNF a and contractile agonists such asacetylcholine can induce reorganization of the actincytoskeleton, a process mediated by the Rho familyof guanosine triphosphatases (GTPase), RhoA andcdc42 [46,47] . Inflammatory mediators and agonistsalso activate ribosomal S6 kinase, p38MAPK. Inhibi-tion of p38MAPK reduces agonist-induced force

generation, possibly through effects on heat shock protein 27, an actin-capping protein [48,49] . A moredetailed discussion of the effects of mediators on theactin cytoskeleton has recently been published [50].

Proinflammatory cytokines affect ASM contrac-tility on many levels. Alterations in calcium homeo-stasis and sensitivity, as well as contractile agonist receptor expression and signal transduction pathways,have profound effects on airway hyperreactivity. Theidentification of the fundamental signaling pathways promoting ASM excitationcontraction coupling will provide new therapeutic targets to modulate ASMfunction in asthma.

Cellular and molecular mechanisms regulatingairway smooth muscle cell growth

Early studies of the histopathology of asthmadescribed increases in both size and number of airwaysmooth muscle cells [51,52] and a correlation be-tween airway hyperreactivity and increased airwaysresistance. During the past decade, significant ad-vances have been made in identifying the manydiverse mitogens and signal transduction pathwaysthat modulate ASM growth (reviewed in [53]). This

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section examines the critical signaling pathways that regulate ASM growth.

Hyperplasia

Animal models of allergic airway inflammationhave shown clear indications of in vivo ASM cell proliferation, using various markers such as bromo-deoxyuridine (Br DU) or proliferating cell nuclear antigen (PCNA) [53]. Studies of bronchial biopsiesfrom patients who had asthma, however, have yieldedconflicting results regarding the presence of ASM proliferation in vivo [5456] . These differences may be caused by sampling error or compartmentalizationof the proliferative response [53] .

MediatorsMany inflammatory mediators are increased in bronchoalveolar lavage (BAL) fluid from airwaysof patients who have asthma, and such mediatorsinduce ASM mitogenesis in vitro [57]. To date, mito-genic stimuli include growth factors such as epider-mal growth factor (EGF), insulin-like growth factors(IGFs), platelet-derived growth factor (PDGF) iso-forms BB and AB, and basic fibroblast growth factor; plasma- or inflammatory cell-derived mediators, suchas lysosomal hydrolases ( b-hexosaminidases andb-glucuronidase), a -thrombin, tryptase, and sphingo-sine 1-phosphate; and contractile agonists, such ashistamine, endothelin-1, substance P, phenylephrine,serotonin, thromboxane A 2 , and LTD4. TGFb in-hibits mitogen-induced ASM cell proliferation [58] but also increases expression of the leukotriene re-ceptor cysLT1R, thereby rendering cells responsive tothe proliferative effects of LTD 4 [59]. Expression of peroxisome-proliferator activated receptor gamma(PPAR- g) is increased in the smooth muscle of pa-tients who have asthma [55]; PPAR- g ligands inhibit mitogen-induced ASM mitogenesis by preventing cell

cycle progression [60].Although IL-1 b, IL-6, and TNF a are also in-creased in the BAL fluid of asthmatics [61], whether these cytokines stimulate ASM proliferation in vitroremains controversial. IL-1 b and IL-6 may inducehyperplasia and hypertrophy of cultured guinea pig or rat ASM cells [62,63] , but other studies have shownthat IL-1 b [64] and IL-6 [65] are nonmitogenic for human ASM cells. The effects of TNF a on ASM proliferation are controversial. McKay and colleagues[65] reported that TNF a had no immediate mitogeniceffect on human ASM cells, in contrast to thefindings of Stewart and colleagues [66] that the proliferative effect of TNF a on human ASM cellsseemed to be biphasic [65,66] . New evidence reveals

that the inhibitory effect of TNF a on ASM prolifera-tion is caused, in part, by autocrine release of IFN b[67] as well as by cytokine-induced production of cyclo-oxygenase 2dependent prostanoids, such as prostag landin E2 (PGE 2), which inhibit DNA syn-thesis [64]. Agonist-induced release of PGE 2 issignificantly lower in smooth muscle derived fromasthmatics than in smo oth muscle obtained fromnonasthmatic persons [68] . Therefore, cytokine-induced proliferative responses in ASM may beenhanced under conditions of cyclo-oxygenase inhibition, in which the expression of growth-inhibitory prostanoids, such as PGE 2, is limited [62,64,66] .

Extracellular matrixExtracellular matrix (ECM) modulates mitogen-

induced ASM cell growth. Collagen types I, III,and V, fibronectin, tenascin, hyaluronan, versican, andlaminin are increased in the airways of asthmatics[69]. In vitro, fibronectin and collagen I increasehuman ASM cell mitogenesis in response to PDGF-BB or a -thrombin, whereas laminin inhibits prolifera-tion [70]. In addition, the increase in cell proliferationis accompanied by decreased expression of smoothmuscle cell contractile proteins such as a -actin,calponin, and myosin heavy chain, suggesting that matrix may also modulate smooth muscle phenotype[70]. ECM composition also affects ASM cell sur-vival. Fibronectin, laminin, and collagens I and IVwere identified as important antiapoptotic elements,whereas elastin promoted ASM apoptosis.

Recently, human ASM cells were shown to se-crete ECM proteins in response to asthmatic sera[71], identifying ASM as a cellular source for ECMdeposition in airways and suggesting a novel mecha-nism by which ASM cells may modulate autocrine proliferative responses. ASM cells from asthmatic pa-tients secrete significantly more perlecan, collagen I,and chondroitin sulfate and less laminin a 1 and col-

lagen IV than ASM cells from nonasthmatic persons[72]. In addition, ECM derived from ASM of asth-matics induces greater cell proliferation than that obtained from nonasthmatics. In contrast, conditionedmedia from either asthmatic or nonasthmatic ASM promote a similar degree of cell proliferation.

Mitogenic signaling pathwaysASM mitogens may act through different recep-

tor-operated mechanisms. Growth factors induceASM cell mitogenesis by activating receptors withintrinsic receptor tyrosine kinase (RTK) activity,whereas contractile agonists released from inflam-matory cells mediate their effects by activationof GPCRs.



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Despite disparate receptor-operated mechanisms,recent evidence suggests that the small GTPase, p21ras, acts as a point of convergence for diverseextracellular signal-stimulated pathways in ASMcells (Fig. 2) [73]. In their active state, p21ras pro-teins interact with downstream effectors, namely,Raf-1 and phosphatidylinositol 3-kinase (PI3K). Byrecruiting Raf-1 to the plasma membrane, guanosinetriphosphatebound p21ras activates the extracellular signal-regulated kinase (ER K) pathway. p21ras also binds and activates PI3K [74]. Synergy can occur between RTK and GPCRs to promote human ASMmitogenesis and p21ras activation [75]. Althoughalternative pathways do exist (as discussed later),PI3K and ERK activation seems to be the dominant signal transduction pathways for RTK-, GPCR- or

cytokine-stimulated growth of ASM cells.PI3K phosphorylates membrane phosphoinosi-tides, which function as second messengers and acti-vate downstream effector molecules, such as 70-kdribosomal S6 kinase (p70 S6k ), Rac1, or Cdc42 toregulate cell cycle protein expression and thus modu-late cell cycle traversal [76] . Activation of PI3K is

critical for ASM cell cycle progression [7779] ;however, although active PI3K is sufficient to stimu-late ASM DNA synthesis, other signaling events arealso necessar y to promote maximal ASM growth re-sponses [80].

As mentioned previously, Raf-1 activation in-duces phosphorylation and activation of mitogen-activated protein (MAP) kinase/ERK kinase (MEK1).Activated MEK1 directly activates the 42-kd ERK2and 44-kd ERK1, collectively referred to as p42/p44MAP kinases. Inhibition of MEK1 and ERK activityattenuates mitogen-induced DNA synthesis in ASMcells, suggesting that activation of MEK1 and ERK isrequired for proliferation [81,82] . Studies such asthese suggest that the ERK pathway is a key signalingevent mediating mitogen-induced ASM proliferation.

D-type cyclins (cyclins D1, D2, and D3) are keyregulators of G 1 progression in mammalian cells;consequently, cyclin D1 has been the most widelystudied cyclin in ASM biology. Another critical protein is p27 Kip1 , a cell cycle inhibitor [83]. A coor-dinated increase of cyclin D1 expression promotescomplexing of unbound p27 Kip1 molecules with cy-clin D-dependent kinases, thereby facilitating cyclinEcyclin-dependent kinase-2 activation later in theG1 phase (Fig. 3) [83].

Recent studies also have implicated the RhoGTPases, Rac1, Cdc42, and RhoA in cyclin D1regulation and ASM growth. Over expression of thecatalytically active subunit of PI3K was sufficient toactivate the cyclin D1 promoter and could be attenu-ated by inhibitors of Rac1 signaling [84], suggestingthat Rac1 may be downstream of PI3K; further studyis necessary to confirm this observation. Other studiesusing overexpression constructs of Cdc42, RhoA, andRac1 also showed that overexpression of Cdc42 or Rac1, but not of RhoA, induced transcription fromthe cyclin D1 promoter in an ERK-independent manner [85,86] .

Although cyclin D1 expression may be necessaryfor cell growth, it is not sufficient. Amrani andcolleagues [87] demonstrated that IFN g inhibits ASMgrowth without modulating the growth factor induced increased expression of cyclin D1. In humanASM, corticosteroids reduce mitogen-stimulated in-creases in cyclin D1 protein and attenuate pRb phosphorylation [88]. Corticosteroid binding to theglucocorticoid receptor results in activation of thetranscription factor C/EBP a and subsequent in-creased expression of cyclin-dependent kinase in-hibitor p21 WAF/Cip1 , thus providing a potentialmechanism for the antiproliferative effect of gluco-corticoids on ASM cell growth [8991] . A recent study suggests that ASM cells derived from patients

Fig. 2. Intracellular pathways regulating ASM cell mito-genesis. Ras serves as a point of convergence for growthfactor receptor tyrosine kinase (RTK) and G-protein coupled receptor (GPCR) signaling. Ras activates theextracellular signal-regulated kinase (ERK) and phosphati-dylinositol 3-kinase (PI3K), and ultimately leads to activa-tion of cyclins and cyclin-dependent kinases (CDKs). MEK,mitogen-activated protein kinase/ERK kinase; p70S6K,ribosomal S6 kinase; ROS, reactive oxygen species.



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who have asthma lack expression of C/EBP a and aretherefore resistant to the effects of glucocorticoids on proliferation [92].

Despite evidence suggesting that oxidative stress

plays an important part in regulating vascular smoothmuscle [93], less is known about the role of reactiveoxygen species in ASM cell function. Brar andcolleagues [94] demonstrated that ASM cells expressseveral components of the phagocyte NADPH, in-cluding gp22phox, gp91phox, and gp67phox. Reac-tive oxygen species can modulate mitogen-inducedASM cell proliferation [86,95,96] . Antioxidants in-hibit mitogen-induced growth [95,96] , whereas expression of a constitutively active Rac1 (another component of the NADPH oxidase complex) resultsin cyclin D1 expression [86]. Decreased expressionof gp22phox by antisense oligonucleotides alsoinhibits ASM cell proliferation [94]. Stat3 also has been shown to be important in PDGF-induced pro-

liferation of human ASM cells. Activation of theJAK2 and Stat3 by PDGF seems to be redox depen-dent and affects the proliferative response to mitogen,independent of MAP kinase activation [97]. IFNg and

IFNb activate Stat1/2, JAK1, and Tyk2 in ASM;these cytokines, however, are potent inhibitors of mitogen-induced proliferation, in part through in-creased expression of interferon-gamma-inducible protein 16 (IFI 16) [67,87] .

Hypertrophy

There is renewed attention to the role of increasedmyocyte size or hypertrophy as a mechanism of increased ASM cell mass in asthma. Some media-tors, such as IL-1 b, IL-6, TGF b, angiotensin II, andcardiotrophin I, induce cellular hypertrophy in vitro,although the mechanisms remain unclear [62,98,99] .In a primate model of asthma, the airways of mon-

Fig. 3. Activation of cell-cycle progression in ASM cells. Activation of cyclin D1 by growth factors or G-proteincoupledreceptor (GPCR) agonists leads to phosphorylation of retinoblastoma protein (Rb) and cell cycle progression. E2F, elongationfactor 2; RTK, growth factor receptor tyrosine kinase.



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keys sensitized to house dust mite antigen display anincrease in smooth mus cle mass as well as in smoothmuscle bundle size [100] . Morphologic studiesconfirm the presence of ASM cell hypertroph y insome, but not all, patients who have asthma [51].Increased cell size seems to correlate negativelywith postbronchodilator forced expiratory volume in1 second and distinguishes betwe en severe persistent asthma and milder dis ease [101] . In contrast, Wood-ruff and colleagues [56] studied ASM cell geneexpression and cell morphology in bronchial biopsiesobtained from patients who had mild to moderateasthma. These investigators found no evidence for ASM cell hypertrophy, although they did confirm the presence of ASM hyperplasia. More work is neededin this particular area of ASM cell biology.

Smooth muscle migration

Hyperplasia and hypertrophy are important pro-cesses regulating increased smooth muscle mass inasthma. Analogous to vascular smooth muscle mi-gration in atherosclerosis, however, ASM cell migra-tion probably promotes airway remodeling in chronicasthma. Evidence suggests that proliferating smoothmuscle cells migrate along chemotactic gradients.During chronic inflammation, myocyte migrationwould be promoted by exposure of cells to a varietyof cytokines and growth factors, as well as to analtered ECM.

Structurally, myofibroblasts display a phenotypeintermediate between fibroblasts and smooth musclecells, express a -smooth muscle actin, and have theability to secrete matrix proteins such as collagen andhyaluronan. In addition, myofibroblasts secrete che-mokines and prolong eosinophil survival [102] . Al-though myofibroblasts are found in the laminareticularis, the origin of these cells remains unknown.Possibly the cells exist in small numbers within the

lamina reticularis and proliferate locally followingstimulation with inflammatory mediators or growthfactors. Alternatively, under the influence of similar stimuli, smooth muscle cells might migrate from the periphery of the smooth muscle bundle into the sub-mucosa. A final possibility is that cells are recruitedfrom a circulating pool of fibrocytes, as has beendescribed by Schmidt and colleagues [103] . In thisstudy, CD34+ cells expressing procollagen I anda -smooth muscle actin were increased in the bron-chial mucosa following allergen challenge in patientswho had asthma. Using a murine model of chronicallergic airway inflammation, the investigators dem-onstrated that these cells were recruited from a cir-culating population of CD34+ fibrocytes.

The potential for mesenchymal cells such as myo-fibroblasts to migrate into the airway wa ll is wellestablished in patients who have asthma [104,105] .BAL-derived fibroblasts from patients who have mildasthma have enhanced migratory capacity comparedwith tissue fibroblasts isolated from bronchial biop-sies [106] . In vitro, many studies support the capacityof ASM cells to migrate. Increased chemotaxis of ASM cells has been demonstrated to PDGF, TGF b, basic fibroblastic growth factor, and IL-1 b. Urokinasehas been shown to increase chemotaxis in some, but not all, studies [107,108] . Cysteinyl-leukotrienesalone promote chemokinesis only; however, in combination with PDGF, increased chemotaxis is ob-served over PDGF alone [109] . Vascular endothelialgrowth factor (VEGF), a potent inducer of vascular

smooth muscle migration, has no effect on ASM cellchemotaxis [110,111] . Similarly, not all mitogens are promigratory; recent data demonstrate that onlyPDGF, but not EGF or thrombin, induce migrationin ASM cells [112] . The ECM also regulates themigratory phenotype, but its role in ASM migrationhas not been extensively characterized. Parames-waran and colleagues [113] recently demonstratedthat ASM cells migrate more on collagen III and Vand fibronectin than on collagen I, elastin, or laminin.

The signaling pathways regulating ASM cellmigration are beginning to be elucidated. Earlystudies suggested that p38 MAP kinase and heat shock protein 27 are important regulators of growthfactor and cytokine-induced migration [114] . Acti-vation of p38 MAP kinase seems to occur, in part,through p21-activated protein kinases [115] and isimportant for phosphorylation of caldesmon, whichacts to regulate actin myosin interactions [116] .Subsequent studies have demonstrated that PI3K alsoregulates PDGF-induced smooth muscle cell migra-tion [110] . PI3K is activated in part through ac-tivation of Src kinase, because inhibition of Src

attenuates PI3K activity [112] . Others have shownthat ASM migration on collagen I, but not on elastinor laminin, is associated with activation of Src [113] .These observations suggest that PDGF-induced mi-gration optimally requires activation of both Src and p38 MAP kinase.

Synthetic function of airway smooth muscle

The previous discussion has focused on theinfluence of cytokines and growth factors on ASMcontractility and proliferation, but ASM cells alsoexpress a variety of secreted cytokines, chemokines,



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and immunomodulatory proteins; this expression istermed synthetic function ( Table 1 ). The syntheticfunction of ASM may play a considerable role inmodulating airway inflammation and remodelingin asthma.

Extracellular matrix

ECM proteins are critical for maintaining thestructure and function of the airways. ASM cells, by producing ECM components as well as matrix-modifying enzymes, may contribute to airway re-modeling. Alterations in the ECM, in turn, modify thegrowth and synthetic function of ASM cells.

The composition of the ECM is tightly controlledand involves a dynamic process of matrix depositionand degradation. In inflammatory processes such asasthma, this balance is disturbed, resulting in anabnormal amount of matrix deposition and also in analtered composition of matrix components. ASMcells secrete a wide variety of matrix proteins, in-

cluding fibronectin, collagen, hyaluronan, laminin,and versican. In asthma, there is an increase in hyal-uronan, fibronectin, tenascin, versican, laminin, andcollagen types I, III, and V [117,118] . In vitro, serumfrom asthmatic patients increases smooth muscle cellrelease of fibronectin, laminin, perlecan, and chon-droitin sulfate [71]. Treatment of cells with cortico-steroids had no effect on the production of matrix proteins by ASM cells [71]. This finding has been borne out in human studies in which inhaled cortico-steroids had minimal effect on altering ECM compo-sition in asthmatics [119] .

TGFb is secreted from ASM cells and, in turn,induces smooth muscle cell synthesis of hyaluronanand collagen [98,120,121] . The mechanism of this

effect probably involves induction of connectivetissue growth factor (CTGF) by TGF b [122] . Recent studies have demonstrated that ASM cells also se-crete VEGF, a potent endothelial mitogen [111,123] .In vitro, VEGF increases fibronectin expression byASM but has no effect on migration or proliferation[111] . Finally, LTD 4 and EGF increase expression of versican and fibronectin in ASM cells [124] .

Increased matrix deposition seen in asthma is probably caused by increased secretion by mesen-chymal cells as well as by an imbalance betweenmatrix-degrading enzymes and inhibitors of these proteases. One class of proteins that has beenintensively studied is the matrix metalloproteinase(MMP) family. MMP-1 expression is elevated in thesmooth muscle cells of patients who have asthma,and studies have shown that LTD 4 increases expres-sion of MMP-1, which acts to degrade insulin-likegrowth factor binding protein, a growth inhibitor [125] . Progelatinase A (MMP-2) is constitutivelyreleased by ASM cells but remains inactive becauseof high levels of tissue inhibitor of metalloproteinases

(TIMP)-2 on the cell membrane [126] , althoughthrombin has been shown to activate MMP-2 [127] .In contrast, TIMP-1 is secreted in large amounts intothe conditioned media of ASM cells [126] . Mem- brane type 1 MMP is also found on ASM [126,127] ;this proteinase can activate MMP-2 and has beenshown to cleave CD44 from the cell surface and promote cell migration [128] . ASM cells also express pro- and active MMP-3 [127] , whereas TNF a in-duces the release of MMP-9, which can degradematrix but also plays a critical role in cleaving latent TGF-b to its active form [129] . ADAMs (a disinte-grinase and metalloproteinase) are a subfamily of metalloproteinases located on the cell surface. Poly-morphisms in the ADAM-33 gene have been asso-

Table 1Airway smooth muscle cellderived factors

Cytokines Chemokines Growth factorsCell adhesionmolecules Extracellular matrix

Matrixmetalloproteinase Other

IL-1b Eotaxin PDGF Integrins Hyaluronan MMP-1 CD40IL-6 IL-8 TGF b ICAM-1 Collagen types I, III, V MMP-2 MHC IIIL-5 MCP-1, 2, 3 VEGF VCAM-1 Laminin MMP-3 PGE 2IL-11 GM-CSF CTGF CD44 Tenascin MMP-9 NOSTNFa RANTES IGF Fibronectin MT-MMP1IFNb TARC Cardiotrophin-1 Perlecan TIMP-1LIF SCF Versican TIMP-2

Fractalkine Decorin ADAM33IP-10 Thrombospondin

Proteoglycan

Abbreviation: IP-10, interferon-inducible protein 10.



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ciated with airway hyperresponsiveness and asthma[130] . ADA M-33 is expressed by ASM cells and lungfibroblasts [130] , although there does not seem to bea significant difference in ADAM-3 3 protein in persons who have asthma and controls [131] .

The composition of the ECM also influencesASM cell function. For example, PDGF-induced pro-liferation is enhanced by monomeric collagen I,fibronectin, and vitronectin, whereas other ECM components, such as fibrillar c ollage n I, collagen III, andtenascin-C, have no effect [132] . Others have shownthat ECM proteins secreted by asthmatic ASM differ from nonasthmatic ASM. Cells plated on the ECMderived from asthmatic ASM displayed greater ratesof proliferation; this finding was true for both non-asthmatic and asthmatic ASM cells [72]. In a study

examining the effect of ECM composition on b2-adrenoceptor signaling in human ASM cells, theinvestigators demonstrated that fibronectin increased,whereas collagen V and laminin decreased, accumu-lation of the second messenger cyclic AMP whencompared with collagens I or IV [133] . This findingsuggests that altered ECM might affect responses to bronchodilator therapy in patients who have asthma.

Chemokine and cytokine release

Many chemokines, which act to recruit andactivate leukocytes, are found in the BAL fluid andlung tissue of patients who have asthma. ASMcells have been shown to secrete RANTES (regulatedon activation, normal T-cell expressed and secreted),eotaxin, IL-8, monocyte chemoattractant protein(MCP)-1, -2, and -3, thymus and activation-regulatedchemokine (TARC), and granulocyte macrophagecolony-stimulating factor (GM-CSF) in response toTNFa and IL-1 b (see Table 1 ). ASM cells may playa role in promoting both the recruitment and survival

of eosinophils by secretion of GM-CSF and IL-5[134136] . ASM infiltration by mast cells also has been shown in patients who have asthma [137] . Inaddition to eotaxin, ASM cells secrete stem cell factor (SCF) [138] , which acts to recruit and retain mast cells within the smooth muscle layer. Release of lipidmediators and enzymes by activated mast cells probably promotes AHR and either inhibits (chy-mase) or promotes (tryptase) ASM cell proliferation[139141] .

IL-6 secretion is inducible by multiple stimuli,including TNF a , IL-1b, and bradykinin, and hasautocrine effects on smooth muscle cell hyperplasia[62]. Transgenic expression of IL-6 in the murinelung induces peribronchiolar inflammation but pro-

motes airway hyporesponsiveness, suggesting acomplex role for IL-6 in modulating local infla mma-tion and regulating airway reactivity [142,143] . Other IL-6family cytokines, such as leukemia inhibitoryfactor (LIF) and IL-11 but not oncostatin M, aresecreted follow ing exposure of ASM cells to viral particles [144] .

T-helper (Th)-2 cytokines IL-4, IL-13, and tosome extent IL-9 have profound effects on ASM cellsynthetic function through induction of a number of signal ing molecules and contractile proteins[145,146] . The Th2 cytokines IL-4 and IL-13 induceeotaxin and, in combination with TNF a , TARC expression [69]. In contrast, IL-4 and -13 have no effect on GM-CSF, RANTES, or IL-8 secretion by ASM[147] . IL-5 and other Th2 cytokines may also play a

role in sensitizing ASM cells to the effects of contractile agonists, independent of their effects onairway eosinophilia [146] . More controversial, per-haps, is the potential for ASM cells to secrete IL-5and IL-13 [13].

Immunomodulatory proteins

Cell adhesion molecules (CAMs) mediate leuko-cyteendothelial cell interactions during the processof cell recruitment and homing [148] . Evidencesuggests that CAMs mediate inflammatory cell stromal cell interactions that may contribute to airwayinflammation. ASM cells express intracellular adhe-sion molecule-1 (ICAM-1) and VCAM-1, which areinducible by a wide range of inflammatory mediators,and constitutively express CD44, a hyaluronan re-ceptor [149] . Recent data suggest that ASM cellsexpress variable levels of integrin subunits, with thea v, a 5, and b1 subunits predominating [150] . b1 sub-units are important in mediating enhanced chemo-kine release by ASM cells adherent to fibronectin or

collagen I [151] .CAMs also function as accessory molecules for leukocyte activation [152] . Whether CAMs expressedon smooth muscle serve this function remains con-troversial, however. Although ASM cells do expressmajor histocompatibility complex (MHC) class II andCD40 following stimulation with IFN g [153,154] ,and a recent study suggests that coculture of T cellswith ASM increases T-cell expression of CD25 [155] ,the physiologic relevance of these findings remainsunknown, because ASM cells are unable to present alloantigen to CD4 T cells [153] .

Functionally, however, adhesion of stimulatedCD4 T cells induces smooth muscle cell DNA syn-thesis [149,156] Ligation of CD40 increases Ca 2 +i ,



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whereas engagement of VCAM-1 on ASM cells aug-ments gro wth factorinduced ASM cell proliferation[154,157] . Enhancement of PDGF-induced prolif-eration by either collagen I or fibr onect in requiresa 2b1, a 4b1, and a 5b1 integrins [132] ; similarly, blocking a 5b1 integrin on ASM cells enhancesapoptosis [150] . Investigators have demonstrated that ASM cells express Fas in vivo and in vitro, andcrosslinki ng of Fas also induces smooth muscle cellapoptosis [158] .

Adhesion of activated T cells also seems toalter smooth muscle cell contractility in a contact-dependent manner [155] , potentially because of theautocrine secretion of IL-5 and IL-1 b [159] . Othershave shown that ASM cells cultured with activatedT cells show increased calcium mobilization re-

sponses to LTD 4 and serotonin [160] . These studieshighlight the finding that direct interactions betweenleukocytes and smooth muscle cells through immuneor adhesion receptors contribute to the modulationof the local milieu resulting in smooth muscle cellactivation and growth.

Increased amounts of exhaled nitric oxide have been detected in patients who have asthma [161] . Nitric oxide seems to have a selective suppressiveeffect on the Th1 subset of Th cells, suggesting that increased levels of nitric oxide may therefore leadto the predominantly Th2-type response associatedwith asthma. Nitric oxide synthase (NOS) has beendemonstrated in cultured ASM cells, where it resultsin an inhibition of ASM cell proliferation [162,163] ,and has been localized to ASM cells in patients whohave asthma [164] . In an animal model, expression of neural nitrous oxide synthase is decreased followingallergen challenge [165] .

ASM cells also secrete PGE 2 and, to a lesser ex-tent, other prostanoids following stimulation with proinflammatory cytokines [166] . PGE2, a potent bronchodilator, also has significant immunologic ef-

fects. For example, PGE 2 can decrease expression of CD23 (Fc gRII), and may have a role as a negativeregulator of airway inflammation and hyperrespon-siveness [167169] . PGE2 inhibits cytokine-inducedsecretion of GM-CSF, RANTES, and CAMs in vitro[170172] and allergen-induced release of PGD 2 in patients who have asthma [173] . In contrast, PGE 2increases IL-6 secretion by ASM cells [174] , primesdendritic cells toward a Th2-promoting capacity,and synergizes with IL-4 to induce IgE synthesis[175,176] .

Receptors for the complement-derived anaphyla-toxin peptides C3a and C5a have also been describedon ASM cells. C3a stimulates enhanced mast celldegranulation following cellcell contact with ASM

cells [177] . These peptides may play an important role in the pathogenesis of asthma by altering airwayhyperresp onsiveness rather than airway inflammation[178,179] . Finally, new data suggest that immuno-stimulatory DNA sequences containing the CpG mo-tif induce Th1-type inflammation, thus suppressingTh2-type respons es that are characteristic of asthma(reviewed in Ref. [180] ). These DNA sequences bindto Toll-like receptors, part of the innate immune sys-tem, and show promise a s pot ential immunotherapyfor airway remodeling [180] . ASM cells expressseveral Toll-like receptors, including Toll-like recep-tor 9, the receptor for CpG (A. Lazaar, unpublisheddata), suggesting that ASM cells play a role in in-nate immunity.

ASM cells provide a rich source of cytokines and

chemokines and, under certain conditions, can express a wide variety of adhesion receptors, costimu-latory molecules, and other immunomodulatory proteins (see Table 1 ). Taken together, these data provide strong support for the potential role of ASMcells in perpetuating airway inflammation and inleukocyte activation.

Summary

The biology of ASM is complex and fascinating.The myriad pathways regulating cell growth and proliferation, combined with the expanding under-standing of the role of ASM as a modulator of in-flammation, provide a rich area of investigation.Future studies will focus on mechanisms regulatingacute inflammation and the chronic repair processesresulting in airway remodeling. These studies may provide the basis for the development of new therapeutic agents aimed at modulating the pathophysio-logical changes associated with asthma.

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