Open access peer-reviewed chapter

Role of Airway Smooth Muscle Cells in Asthma Pathology

Written By

Wenchao Tang

Submitted: October 15th, 2018 Reviewed: January 13th, 2019 Published: February 13th, 2019

DOI: 10.5772/intechopen.84363

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Airway smooth muscle (ASM) cells have been shown to play an important role in bronchial asthma. As the research progresses, the mechanism becomes more and more complex. This chapter reviews the role of ASM in asthma pathological mechanisms including inflammatory reaction, extracellular matrix proteins, cell contraction, cell structure, neuromodulation, airway remodeling, apoptosis, autophagy, miRNA, mitochondria, etc. In brief, ASM is similar to a “processing station.” It is not only affected by various signals in the body to produce biological effects and secrete various signals to act on downstream target cells but also feeds back to the upstream pathways or receives feedback from downstream pathways to form a complex network. The results summarized in this chapter are expected to provide new targets for the clinical treatment of asthma.


  • airway smooth muscle cells
  • asthma
  • inflammation
  • airway hyperreactivity
  • airway remodeling

1. Introduction

Bronchial asthma is a chronic airway inflammatory disease involving a variety of airway inflammatory cells, airway structural cells, and cellular components of which airway smooth muscle (ASM) cells have received the most intensive investigation. ASM has been shown to play an important role in the structure, function, and contraction of the airways. Evidence suggests that some ASM signaling mechanisms can help regulate the release of pro-inflammatory and anti-inflammatory mediators, which are factors that regulate immunity; different types of airway cells (such as epithelial cells, fibroblasts, and nerve cells); intracellular Ca2+ concentration-mediated airway contraction and relaxation; cell proliferation and apoptosis, autophagy, production, and regulation of the extracellular matrix (ECM); and neuromodulation. These mechanisms cause structural changes in the narrowing and dilatation of the airway, resulting in airway hyperreactivity (AHR) and airway stenosis, hence affecting airway compliance.


2. ASM participates in asthma by releasing pro-inflammatory or anti-inflammatory factors and immune regulators

ASM can produce a variety of pro-inflammatory and anti-inflammatory factors triggered by inflammation, injuries, and microbial products [1], including interleukin-1β (IL-1β), IL-5, IL-6, IL-8, IL-17, platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), etc., which constitute a complex network that participates in airway inflammation. For example, IL-6 induces ASM cell proliferation and further modulates immune cell function [2], and TNF-α exerts its mediating effects by enhancing interferon (IFNβ) secretion [3]. Recent studies have confirmed that ASM can produce and release thymic stromal lymphopoietin (TSLP) and can also act as a target of TSLP to participate in the recruitment of dendritic cells to regulate airway immune responses [4, 5]. ASM cells also produce chemokines such as RANTES and eotaxin [6]. The specific mechanism may be mediated by mitogen-activated protein kinase (MAPK), janus kinase/signal transducer and activator of transcription protein signaling pathway (JAK/Stat), and c-jun N-terminal kinase (JNK) [7, 8]. There is also evidence that ASM can also secrete growth factors such as vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BNDF), and these growth factors may be involved in ASM proliferation and contraction through autocrine effects [9].


3. ASM acts on asthma by secreting extracellular matrix (ECM)

The action of ASM ECM proteins on airway remodeling by autocrine or paracrine effects is a current research focus in asthma. ASM can produce a series of ECM proteins [10]. In the airway, ECM proteins surround cells in the form of reticular collagen or noncollagen, and their density and structure affect cellular characteristics such as proliferation, migration, differentiation, and survival. The related components include collagen, fibronectin, the matrix metalloprotein (MMP) family (MMP-2, MMP-3, MMP-9, MMP-13, etc.), and metalloprotein antagonists (TIMP-1 and TIMP-2) (Figure 1) [1, 11, 12]. Meanwhile, ECM protein signaling groups can in turn regulate other cells such as epithelial cells and ASMs. The ECM can control its own conformation, release growth factors, and MMPs and regulate the activity of local growth factors (such as neurotrophin and VEGF) and cytokines by cleavage and inactivation [13], thereby forming a complex signaling network to regulate airway remodeling. For example, IL-1β can interact with tumor necrosis factor-α (TNF-α), thus increasing MMP-12 [14] and MMP-9 [15], promoting cell migration and remodeling, and further regulating growth factor activity.

Figure 1.

MMP and TIMP mRNA expression by qRT-PCR five primary ASM cell cultures and expressed relative to GAPDH. It was originally published on “Matrix metalloproteinase expression and activity in human airway smooth muscle cells” of the British Journal of Pharmacology by Shona R. Elshaw et al.

In terms of the regulatory mechanisms of the ECM, Rho kinase inhibitors can prevent ECM-induced airway remodeling [16]. The Wnt/β-catenin pathway can regulate TGF-β regulation of ASM-derived ECM [1, 17]. In contrast, decorin (an ECM proteoglycan) binds to TGF-β and reduces ECM production [18]. Even infections can regulate ECM products via ASM, and rhinovirus-induced infections increase fibronectin and basement membrane glycans, especially in the ASM of asthma patients [19]. Thus, altering the production of ECM, thereby modulating the inflammatory mediators or growth factors produced by the ASM or other cells, may result in cross reaction of airway structures and functions.


4. ASM is involved in asthma through other mechanisms

In addition to inflammatory mediators and growth factors, many emerging mechanisms have been reported to be involved in ASM and airway remodeling. For example, vitamin D has been shown to inhibit remodeling in vitro and in vivo [20]. However, its mechanism involving airway ASM cells is still under investigation [21]. Another emerging mechanism is thyroxine, which has been reported to enhance ASM proliferation [22], while low thyroxine levels cause airway developmental malformations [23]. Some reports also suggest that insulin appears to enhance ASM proliferation and ECM formation [24]. In addition, sphingolipids participate in airway inflammation, AHR, and remodeling. In particular, sphingosine-1-phosphate can promote ASM contractility and regulate inflammation and airway remodeling [25, 26].


5. Roles of ASM, [Ca2+]i, and contraction mechanisms in asthma

The cytosolic Ca2+ concentration ([Ca2+]i) is a well-established pathway for the regulation of ASM contraction. The [Ca2+]i can affect voltage-gated channels, receptor-regulated channels, and calcium pool-regulated channels. These channels are subjected to regulation by pathways such as phospholipase C (PLC), inositol triphosphate (IP3), ryanodine receptor (RyR), etc. (Figure 2). Meanwhile, sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), bidirectional Na+-Ca2+ exchangers (NCX), and mitochondrial buffers can limit [Ca2+]i and regulate calcium storage by inhibiting the activation of [Ca2+]i. In addition to [Ca2+]i, Ca2+-calmodulin-dependent myosin light chain (MLC) kinase and MLC act in tandem to regulate ASM contractility by excitatory myosin interaction. Studies have shown that the Rho-associated coiled-coil containing kinases (ROCK) pathway inhibits the contraction of Ca2+-sensitive cells by inhibiting the sensitivity of MLC kinase [27]. IP3 can activate Ca2+ influx [28] in ASM and regulate local Ca2+ release [29].

Figure 2.

Signaling pathways of Ca2+ concentration in ASM involving IP3R and RyR and the potential targets of mabuterol hydrochloride (Mab) that intervene in the increased level of intracellular Ca2+ induced with Ach. Binding with a G-protein-coupled receptor, Ach activates PLC to generate IP3, which encourages the clusters of IP3R on SR to release Ca2+. RyR may also be activated or potentiated by cADP ribose (cADPR). It may be sequestered by the superficial sarcoplasmic reticulum (SR) through sarcoendoplasmic Ca2+ ATPase 2a (SERCA2a), although much of the calcium is released from stores and enters the cytoplasm. The increased level of intracellular Ca2+ leads to the contraction, proliferation, and migration of the ASM. It was originally published on “Matrix metalloproteinase expression and activity in human airway smooth muscle cells” of the British Journal of Pharmacology by Shona R. Elshaw et al. It was originally published on “Suppression of the increasing level of acetylcholine-stimulated intracellular Ca2+ in guinea pig airway smooth muscle cells by mabuterol” of Biomedical Reports by Xirui Song et al.

5.1 GPCR mechanism and asthma

G-protein-coupled receptors (GPCRs) are a superfamily of cell membrane proteins that transduce extracellular signals, causing intracellular cascades and leading to different cellular functions. This mechanism is used to treat diseases such as asthma and chronic obstructive pulmonary disease (COPD). In ASM, most of the existing research focuses on the expression and function of different GPCRs (Gq, Gi, and Gs) in ASM contraction/relaxation. For instance, traditional bronchoconstrictor agonists such as acetylcholine (ACh), histamine, and endothelin act through the Gq-coupled pathway, activating the PLC-IP3 pathway and thereby increasing Ca2+. However, bronchiectasis caused by the Gs-coupled pathway (increasing cAMP) is the major mechanism of action of the β2-adrenergic receptor [30]. Moreover, GPCRs alone or in combination with other pathways, such as receptor tyrosine kinases acting through cell proliferation/growth, secretion of growth factors, and inflammatory mediators, promote the “synthesis function” of ASM, and its remodeling of airways is gaining increasing attention [31].

The current common GPCRs include gamma-aminobutyric acid (GABA), calcium-sensing receptor (CaSR), thromboxane (TXA2), bitter taste receptor (BTR), and prostaglandin E2 (PGE2). The present research status is summarized as follows.

GABA is a major inhibitory neurotransmitter in the mammalian central nervous system and activates both the ligand-gated ionotropic GABAA receptor and the G-protein-coupled metabotropic GABAB receptor. Functional GABAB receptors are present in ASM [32, 33] and airway epithelium [34]. GABAB produces airway contraction through Gi, and the GABAA receptor on ASM appears to be a potent bronchodilator [35]. Since the human ASM GABAA receptor only expresses the α4 and α5 subunits, recent studies have shown that selective targeting of the ASM GABAA receptor can improve the efficacy of anti-asthmatic drugs and minimize side effects [36]. The reported data suggest that the heterogeneity of selective targeting of ASM GABAA receptor features is a novel approach to bronchiectasis.

CaSR, a GPCR, is often expressed in non-Ca2+-regulated tissues such as blood vessels and breasts and can regulate the extracellular Ca2+ concentration ([Ca2+]e), gene expression, ion channels, and ECM through the parathyroid glands, kidneys, and bones. Abnormal expression of CaSR is usually associated with inflammation, vascular calcification, and tumors. Although CaSR is important in the development of the lungs, studies on the expression or function of CaSR in the airways are still rare. CaSR has been reported to be expressed in the developing airway epithelium [37] and regulates the morphology of the lung bronchus through [Ca2+]e levels, thereby affecting tracheal remodeling [38]. In adults, CaSR is present in the human respiratory tract, especially in ASM, and CaSR expression is increased in ASM of asthmatic subjects [39], which may become a new target for future asthma treatment. Depending on the cell type, the expression and function of CaSR are regulated by signaling pathways such as ROCK, extracellular signal-regulated kinase (ERKs), and protein kinase C (PKC) [40]. Therefore, this receptor can be considered a multimode sensor and effector for the integration of composite signals and has an important impact on airway structure and function.

TXA2 is a potent endogenous bronchoconstrictor that is observed to have increased levels in asthmatic airways [41]. TXA2 induces and enhances the contraction of allergic bronchi primarily through interaction with the thromboxane prostaglandin (TP) receptor coupled to Gq and the PLC/IP3/Ca2+ pathway. Studies have shown that the TXA2 effector mechanism is complex and involves indirect effects of neuronal stimulation leading to ACh release and mechanical stimulation [42].

The BTR is a recently discovered bronchodilator. It was originally thought to act through the taste 2 receptors (TAS2R) family of GPCRs to increase [Ca2+]i and induce bronchiectasis [43]. TAS2Rs exhibit low specificity and affinity for a wide range of bitter compounds, and the corresponding result is a diversity of signal combinations. Factors affecting TAS2Rs include agonist concentration and receptor desensitization [44]. BTR can induce membrane hyperpolarization [45] via the blocker-sensitive Ca2+-activated K-channels [43, 46] and nonselective cation channels and interact with specific bronchoconstrictors [46]. Moreover, studies have suggested that BTRs can activate different Ca2+ signaling pathways under specific conditions. For example, TAS2R stimulation activates Gβγ under baseline conditions to increase [Ca2+]i [47]. Other studies have also shown that the bronchodilating effect of BTR may also depend on interactions with β2-adrenergic receptor expression and signaling [48]. When TAS2R is activated, relaxation can be induced even under adrenergic receptor desensitization [48], which may be an alternative treatment method for asthma patients with bronchiectasis who are desensitized to β-agonists. Through extensive research, BTR has also been shown to affect genetic variations that result in sinusitis and asthma [49]; the mechanism by which BTR relaxes the airway has not yet been elucidated.

PGE2 and its epoprostenol (EP) receptor subtype are produced by airway epithelium and ASM and have complex effects on bronchoconstriction and expansion. Previous studies have shown that endogenous PGE2 has a bronchial protective effect in asthma. The PGE2 signal acts through four different GPCRs (EP1–EP4). Since different pathways have different G-protein coupling and downstream signals, and some downstream pathways can counteract each other [50], the mechanism of action is complicated. Studies have shown that EP1 increases Ca2+ and EP3 reduces cAMP synthesis, leading to ASM contraction, while EP2 and EP4 induce bronchodilation by increasing cAMP. In addition, EP3 can also cause an opposite reaction by promoting ASM migration [51].

In addition to the above GPCR-related mechanisms, many studies have been performed on Wnt signaling in the airways in recent years. Wnt proteins act through coreceptors such as lipoprotein receptor-associated protein (LRP)-5/LRP-6, receptor-like tyrosine kinase (Ryk), and receptor tyrosine kinase-like orphan receptor 2 (Ror2) to promote binding to the extracellular domain of the frizzled (Frz) family of GPCRs. The Wnt signaling pathways include the classical β-catenin-dependent and β-catenin-independent pathways and the noncanonical Wnt/Ca2+ pathway. In ASM, Wnt signaling is thought to be closely related to airway remodeling [52]. In fibroblasts, Wnt5B can increase the secretion of IL-6 and chemokine ligand 8 (CXCL-8) and indirectly affect airway remodeling (69). In epithelial cells, Wnt signaling in inflammation produces ECM and indirectly induces remodeling [53].

5.2 Non-GPCR mechanisms and asthma

Regarding airway contraction controlled by non-GPCR mechanisms, the mechanism of Ca2+ signaling regulation has been intensely investigated. For example, calcineurin can regulate local Ca2+ signaling and contractility in ASM. Meanwhile, the Ca2+ influx channel TRPC3 can activate the calcineurin/nuclear factor of activated T cells (NFAT) pathway to regulate airway contraction [54].

In addition, ASM can also express some specific receptors such as the transient receptor potential ankyrin 1 (TRPA1) or polysaccharides for non-GPCR-mediated airway regulation. In particular, TRPA1 and capsaicin receptor 1 (TRPV1) channels can be activated by PKC resulting in neuromodulation of airway contraction [55]. Studies have shown that ASM expresses TRPA1 [56] and TRPV1 [57] as well as TRPV4 [58, 59]. TRPA1 has been shown to promote IL-8 secretion in ASM, enhance airway inflammation and AHR [60], and mobilize [Ca2+]i [56] while inhibiting the proliferation of ASM [61]. In contrast, TRPV1 appears to promote proliferation [62]. TRPV4 is associated with an increase in [Ca2+]i [59] and ASM contraction and proliferation (Figure 3) [58, 63]. In addition to TRPA, ASM can also express epidermal growth factor receptor (EGFR) and hyaluronic acid to participate in airway inflammation [64]. The expression of hyaluronic acid is increased during inflammation [65] and is involved in the homeostasis of aqueous fluids, cell matrix signaling, cell proliferation and migration, and regulation of inflammation [66].

Figure 3.

The role of TRP channels in ASM. It was originally published on “Novel drug targets for asthma and COPD: Lessons learned from in vitro and in vivo models” of Pulmonary Pharmacology & Therapeutics by Katie E. Baker et al.


6. ASM cell structure and asthma

Some intracellular and extracellular structures of ASM are closely related to the pathological changes of asthma. Caveolae and their regulatory caveolin and cavin proteins are a focus of research. Caveolae have been shown to contain excitatory contractile receptors and activate Ca2+ influx channels (including transient receptor potential channel (TRPC) subtypes and calcium release-activated calcium channel protein 1 (Orai1)) [67, 68]. The decreased expression of its important component, caveolin-1, induces an increase in ASM [Ca2+]i and a contractile response and promotes ASM proliferation [69]. The relevant mechanisms include a reduction in [Ca2+]i influx, increase in sarcoplasmic reticulum Ca2+ release, and reduction in Ca2+ sensitivity through the RhoA pathway. Conversely, pro-inflammatory factors such as TNF-α can enhance the expression and function of caveolin-1 [70].


7. Proliferation and apoptosis of ASM cells and airway remodeling during asthma

Airway remodeling is an important pathological change in asthma. The increased mass of ASM may be a key feature of airway remodeling, and its hyperplasia and hypertrophy are unevenly distributed in bronchi of different sizes. This process can enhance airway contraction and airway stenosis, further leading to decreased lung function or severe asthma [71]. The underlying causes of ASM hypertrophy have been extensively explored. For example, excessive mechanical stretching can lead to the release of EGF, which participates in remodeling [72]. In addition, Wnt, glycogen synthase kinase 3 beta (GSK3β) [73], or rapamycin target protein (mTOR) [74] may also be involved in the regulation of reconfiguration caused by mechanical forces. Studies have also shown that hypertrophy is associated with increased MLC kinase in ASM [75]. In addition, many signaling pathways have been found to be related to ASM proliferation, including p38, p42/p44 MAP kinase and PI3/Akt.

During the pathogenesis of asthma, some pro-inflammatory mediators are involved in the regulation of ASM proliferation, such as TNF-α, IL-4, IL-5, IL-13, TGF-β, thymic stromal lymphopoietin (TSLP), and Th17 family members. In addition, some conventional stimuli such as agonists of airway bronchial contraction [76] and other locally produced factors [9, 77] may also trigger an increase in proliferation under certain circumstances. Recent studies have shown that a nonreceptor tyrosine kinase, Abl, promotes ASM mitosis and enhances ASM proliferation [78]. It has also been suggested that sex hormones can affect the structure and function of the airway because, in some cases, estrogen can reduce mitosis and exert antiproliferative effects in the airway [79]. In addition, within ASM cells, microRNAs are thought to play an important role in the regulation of ASM cell proliferation and migration [80].

Overall, current information indicates that the interaction of multiple signaling mechanisms leads to airway remodeling represented by ASM cell proliferation. Although many inflammatory pathways can cause cell proliferation, limited data exist regarding how to inhibit or block proliferation. Studies have shown that regulating the ECM (such as the collagen density) or inducing increased expression of caveolin-1 can limit ASM cell proliferation [81] and some therapeutic drugs such as corticosteroids and β2 receptor agonists can also reduce proliferation [82]. In addition, peroxisome proliferator-activated receptor (PPAR)-γ ligands can attenuate ASM proliferation [83].

In the context of airway remodeling, an increase in ASM mass indicates an increase in cell proliferation and reflects a decrease in apoptosis. However, based on the current data, the mechanisms of the two are quite different. Th17-associated cytokines, IL-18, eotaxin, monocyte inflammatory protein-1a [84], and TRPV1 agonists [85] can alleviate ASM apoptosis. Other studies have found that peroxisome proliferator-activated receptor gamma (PPAR-γ) [86], collagen [87], and vitamin D can regulate ASM proliferation without affecting apoptosis.


8. ASM autophagy and asthma

At present, autophagy is considered an adaptive response of cells to survival that can promote cell death in the context of disease. This process is essential in maintaining homeostasis, managing external stress, and regulating cellular capacity. Autophagy plays a major role in the immune response to various pathogens, particularly viruses. In the case of asthma, autophagy in the airway epithelium or ASM may occur in the context of infection [88]. The current research on the role of autophagy in asthma and the types of cells involved is relatively limited. For example, pharmacological inhibition of gamma-glutamyltransferase 1 (GGT1) has been found to induce p53-dependent autophagy in human ASM cells [85]. In addition, excessive reactive oxygen species (ROS) that may be present during airway inflammation can induce autophagy, thus contributing to the pathophysiology of asthma [89].


9. ASM, miRNA, and asthma

Many studies have examined miRNA-mediated regulation of ASM. During the asthma process, many specific miRNAs are thought to play multiple roles in ASM [90]. For example, pro-inflammatory cytokines such as IL-1β, TNF-α, and IFNγ can downregulate 11 miRNAs, particularly miR-25, miR-140, miR-188, and miR-25. In contrast to the above results, another study [80] showed that expression levels of miR-146a and miR-146b were elevated in ASM in an IL-1β, TNF-α, and IFNγ-treated asthma group. Other studies have shown that only miR-146a is an endogenous negative regulator of human ASM cells [91].

In terms of airway remodeling, miR-140-3p regulates the important enzyme CD38 [92], which may have multiple downstream effects, such as affecting [Ca2+]i and proliferation [93, 94, 95]. Under the induction of mechanical elongation, miR-26a causes ASM hypertrophy by attenuating GSK3β [96]. However, ASM proliferation appears to be driven by multiple miRNAs, including miR-10a [97], miR-23b [98], miR-138 [99], miR-145 [100], and miR-203 [101]. In general, we have found many miRNA pathways in ASM, but many problems remain unresolved, and miRNAs will be a focus for targeted asthma therapy in the future.


10. Mitochondria and ASM

Mitochondria in the airway not only produce ATP but are also involved in functions such as Ca2+ buffering [102, 103, 104], endoplasmic reticulum pathways, Ca2+ influx (such as store-operated Ca2+ entry (SOCE)), and cell proliferation and survival. These functions mostly involve fission and fusion of mitochondrial structures, mitochondrial biogenesis, mitochondrial autophagy, and ROS destruction [102, 105]. For example, consumption of mitochondrial DNA attenuates the concentration of [Ca2+]i in ASM [106]. In terms of regulation, TGF-β enhances ASM mitochondrial ROS and promotes cytokine secretion [107]. Conversely, airway inflammation impairs mitochondrial Ca2+ buffering, resulting in an increase in [Ca2+]i. This damage leads to not only an increase in ROS but also an increase in endoplasmic reticulum stress and the unfolded protein response (UPR) [108]. These pathways are relevant because they can further influence protein expression and function as well as airway remodeling [109, 110].

11. Conclusions

With the rapid progress in molecular biology, cell biology, and various experimental techniques, research on ASM has developed rapidly, and an increasing number of functions have been discovered. When investigating ASM, we should consider the presence of surrounding cells and the ECM. Investigation of the role of ASM is no longer limited to its contractility, remodeling, and secretion. ASM is similar to a “processing station.” It not only is affected by various signals in the body to produce biological effects and secrete various signals to act on downstream target cells but also feeds back to the upstream pathways or receives feedback from downstream pathways to form a complex network. Therefore, a univariant study of the mechanism of ASM action is unrealistic. More comprehensive studies integrating bioimaging, informatics, and other technologies are needed to conduct more accurate target interventions, obtain more precise pathway information, and provide new therapeutic targets for asthma.


This work was funded by the National Natural Science Foundation of China (grant number No. 81403469) and the Three-Year Development Plan Project for Traditional Chinese Medicine of Shanghai (grant number No. ZY (2018–2020)-CCCX-2001-2005).

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1. Koziol-White CJ, Panettieri RA Jr. Airway smooth muscle and immunomodulation in acute exacerbations of airway disease. Immunological Reviews. 2011;242(1):178-185
  2. 2. Robinson MB, Deshpande DA, Chou J, Cui W, Smith S, Langefeld C, et al. IL-6 trans-signaling increases expression of airways disease genes in airway smooth muscle. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2015;309(2):L129-LL38
  3. 3. Ye YL, Wu HT, Lin CF, Hsieh CY, Wang JY, Liu FH, et al. Dermatophagoides pteronyssinus 2 regulates nerve growth factor release to induce airway inflammation via a reactive oxygen species-dependent pathway. American Journal of Physiology. Lung Cellular and Molecular Physiology. 2011;300(2):L216-L224
  4. 4. Redhu N, Gounni A. Function and mechanisms of TSLP/TSLPR complex in asthma and COPD. Clinical & Experimental Allergy. 2012;42(7):994-1005
  5. 5. Redhu NS, Saleh A, Halayko AJ, Ali AS, Gounni AS. Essential role of NF-κB and AP-1 transcription factors in TNF-α-induced TSLP expression in human airway smooth muscle cells. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2010;300(3):L479-LL85
  6. 6. Damera G, Tliba O, Panettieri RA Jr. Airway smooth muscle as an immunomodulatory cell. Pulmonary Pharmacology & Therapeutics. 2009;22(5):353-359
  7. 7. Alrashdan YA, Alkhouri H, Chen E, Lalor DJ, Poniris M, Henness S, et al. Asthmatic airway smooth muscle CXCL10 production: Mitogen-activated protein kinase JNK involvement. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2012;302(10):L1118-L1L27
  8. 8. Tan X, Alrashdan YA, Alkhouri H, Oliver BG, Armour CL, Hughes JM. Airway smooth muscle CXCR3 ligand production: Regulation by JAK-STAT1 and intracellular Ca2+. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2013;304(11):L790-L802
  9. 9. Aravamudan B, Thompson M, Pabelick C, Prakash Y. Brain-derived neurotrophic factor induces proliferation of human airway smooth muscle cells. Journal of Cellular and Molecular Medicine. 2012;16(4):812-823
  10. 10. Hirota N, Martin JG. Mechanisms of airway remodeling. Chest. 2013;144(3):1026-1032
  11. 11. Churg A, Zhou S, Wright JL. Series "matrix metalloproteinases in lung health and disease": Matrix metalloproteinases in COPD. The European Respiratory Journal. 2012;39(1):197-209
  12. 12. Kelly EA, Jarjour NN. Role of matrix metalloproteinases in asthma. Current Opinion in Pulmonary Medicine. 2003;9(1):28-33
  13. 13. Ethell IM, Ethell DW. Matrix metalloproteinases in brain development and remodeling: Synaptic functions and targets. Journal of Neuroscience Research. 2007;85(13):2813-2823
  14. 14. Xie S, Issa R, Sukkar MB, Oltmanns U, Bhavsar PK, Papi A, et al. Induction and regulation of matrix metalloproteinase-12in human airway smooth muscle cells. Respiratory Research. 2005;6(1):148
  15. 15. Tran T, Teoh CM, Tam JKC, Qiao Y, Chin CY, Chong OK, et al. Laminin drives survival signals to promote a contractile smooth muscle phenotype and airway hyperreactivity. The FASEB Journal. 2013;27(10):3991-4003
  16. 16. Possa SS, Charafeddine HT, Righetti RF, da Silva PA, Almeida-Reis R, Saraiva-Romanholo BM, et al. Rho-kinase inhibition attenuates airway responsiveness, inflammation, matrix remodeling, and oxidative stress activation induced by chronic inflammation. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2012;303(11):L939-LL52
  17. 17. Bourke JE, Li X, Foster SR, Wee E, Dagher H, Ziogas J, et al. Collagen remodelling by airway smooth muscle is resistant to steroids and β2-agonists. European Respiratory Journal. 2011;37(1):173-182
  18. 18. Marchica CL, Pinelli V, Borges M, Zummer J, Narayanan V, Iozzo RV, et al. A role for decorin in a murine model of allergen-induced asthma. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2011;300(6):L863-LL73
  19. 19. Kuo C, Lim S, King NJ, Johnston SL, Burgess JK, Black JL, et al. Rhinovirus infection induces extracellular matrix protein deposition in asthmatic and nonasthmatic airway smooth muscle cells. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2011;300(6):L951-L9L7
  20. 20. Britt RD Jr, Faksh A, Vogel ER, Thompson MA, Chu V, Pandya HC, et al. Vitamin D attenuates cytokine-induced remodeling in human fetal airway smooth muscle cells. Journal of Cellular Physiology. 2015;230(6):1189-1198
  21. 21. Foong RE, Bosco A, Troy NM, Gorman S, Hart PH, Kicic A, et al. Identification of genes differentially regulated by vitamin D deficiency that alter lung pathophysiology and inflammation in allergic airways disease. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2016;311(3):L653-LL63
  22. 22. Dekkers BG, Naeimi S, Bos IST, Menzen MH, Halayko AJ, Hashjin GS, et al. l-Thyroxine promotes a proliferative airway smooth muscle phenotype in the presence of TGF-β1. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2014;308(3):L301-L3L6
  23. 23. Godbole MM, Rao G, Paul B, Mohan V, Singh P, Khare D, et al. Prenatal iodine deficiency results in structurally and functionally immature lungs in neonatal rats. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2012;302(10):L1037-L1L43
  24. 24. Agrawal A, Mabalirajan U, Ahmad T, Ghosh B. Emerging interface between metabolic syndrome and asthma. American Journal of Respiratory Cell and Molecular Biology. 2011;44(3):270-275
  25. 25. Che W, Manetsch M, Quante T, Rahman MM, Patel BS, Ge Q , et al. Sphingosine 1-phosphate induces MKP-1 expression via p38 MAPK-and CREB-mediated pathways in airway smooth muscle cells. Biochimica et Biophysica Acta - Molecular Cell Research. 2012;1823(10):1658-1665
  26. 26. Che W, Parmentier J, Seidel P, Manetsch M, Ramsay EE, Alkhouri H, et al. Corticosteroids inhibit sphingosine 1-phosphate-induced interleukin-6 secretion from human airway smooth muscle via mitogen-activated protein kinase phosphatase 1-mediated repression of mitogen and stress-activated protein kinase 1. American Journal of Respiratory Cell and Molecular Biology. 2014;50(2):358-368
  27. 27. Liu C, Zuo J, Pertens E, Helli PB, Janssen LJ. Regulation of rho/ROCK signaling in airway smooth muscle by membrane potential and [Ca2+] i. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2005;289(4):L574-LL82
  28. 28. Song T, Hao Q , Zheng Y-M, Liu Q-H, Wang Y-X. Inositol 1, 4, 5-trisphosphate activates TRPC3 channels to cause extracellular Ca2+ influx in airway smooth muscle cells. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2015;309(12):L1455-L1L66
  29. 29. Liu Q-H, Zheng Y-M, Wang Y-X. Two distinct signaling pathways for regulation of spontaneous local Ca2+ release by phospholipase C in airway smooth muscle cells. Pflügers Archiv - European Journal of Physiology. 2007;453(4):531-541
  30. 30. Penn RB, Bond RA, Walker JK. GPCRs and arrestins in airways: Implications for asthma. In: Arrestins-Pharmacology and Therapeutic Potential. Berlin, Heidelberg: Springer; 2014. pp. 387-403
  31. 31. Brandsma C-A, Timens W, Jonker MR, Rutgers B, Noordhoek JA, Postma DS. Differential effects of fluticasone on extracellular matrix production by airway and parenchymal fibroblasts in severe COPD. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2013;305(8):L582-L5L9
  32. 32. Gallos G, Townsend E, Yim P, Virag L, Zhang Y, Xu D, et al. Airway epithelium is a predominant source of endogenous airway GABA and contributes to relaxation of airway smooth muscle tone. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2012;304(3):L191-L1L7
  33. 33. Gallos G, Yim P, Chang S, Zhang Y, Xu D, Cook JM, et al. Targeting the restricted α-subunit repertoire of airway smooth muscle GABAA receptors augments airway smooth muscle relaxation. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2011;302(2):L248-LL56
  34. 34. Mizuta K, Osawa Y, Mizuta F, Xu D, Emala CW. Functional expression of GABAB receptors in airway epithelium. American Journal of Respiratory Cell and Molecular Biology. 2008;39(3):296-304
  35. 35. Croasdell A, Thatcher TH, Kottmann RM, Colas RA, Dalli J, Serhan CN, et al. Resolvins attenuate inflammation and promote resolution in cigarette smoke-exposed human macrophages. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2015;309(8):L888-L901
  36. 36. Gallos G, Yocum GT, Siviski ME, Yim PD, Fu XW, Poe MM, et al. Selective targeting of the α5-subunit of GABAA receptors relaxes airway smooth muscle and inhibits cellular calcium handling. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2015;308(9):L931-LL42
  37. 37. Finney BA, Del Moral PM, Wilkinson WJ, Cayzac S, Cole M, Warburton D, et al. Regulation of mouse lung development by the extracellular calcium-sensing receptor, CaR. The Journal of Physiology. 2008;586(24):6007-6019
  38. 38. Kovacs CS, Kronenberg HM. Maternal-fetal calcium and bone metabolism during pregnancy, puerperium, and lactation. Endocrine Reviews. 1997;18(6):832-872
  39. 39. Yarova PL, Stewart AL, Sathish V, Britt RD, Thompson MA, Lowe AP, et al. Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma. Science Translational Medicine. 2015;7(284):284ra60-284ra60
  40. 40. Riccardi D, Kemp PJ. The calcium-sensing receptor beyond extracellular calcium homeostasis: Conception, development, adult physiology, and disease. Annual Review of Physiology. 2012;74:271-297
  41. 41. Wenzel SE, Westcott J, Smith HR, Larsen GL. Spectrum of prostanoid release after bronchoalveolar allergen challenge in atopic asthmatics and in control groups. The American Review of Respiratory Disease. 1989;139(450):e7
  42. 42. Allen IC, Hartney JM, Coffman TM, Penn RB, Wess J, Koller BH. Thromboxane A2 induces airway constriction through an M3 muscarinic acetylcholine receptor-dependent mechanism. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2006;290(3):L526-LL33
  43. 43. Deshpande DA, Wang WC, McIlmoyle EL, Robinett KS, Schillinger RM, An SS, et al. Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction. Nature Medicine. 2010;16(11):1299
  44. 44. Robinett KS, Deshpande DA, Malone MM, Liggett SB. Agonist-promoted homologous desensitization of human airway smooth muscle bitter taste receptors. American Journal of Respiratory Cell and Molecular Biology. 2011;45(5):1069-1074
  45. 45. Zhang T, Luo X-J, Sai W-B, Yu M-F, Li W-E, Ma Y-F, et al. Non-selective cation channels mediate chloroquine-induced relaxation in precontracted mouse airway smooth muscle. PLoS One. 2014;9(7):e101578
  46. 46. Pulkkinen V, Manson ML, Säfholm J, Adner M, Dahlén S-E. The bitter taste receptor (TAS2R) agonists denatonium and chloroquine display distinct patterns of relaxation of the Guinea pig trachea. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2012;303(11):L956-LL66
  47. 47. Zhang C-H, Lifshitz LM, Uy KF, Ikebe M, Fogarty KE, ZhuGe R. The cellular and molecular basis of bitter tastant-induced bronchodilation. PLoS Biology. 2013;11(3):e1001501
  48. 48. An SS, Wang WC, Koziol-White CJ, Ahn K, Lee DY, Kurten RC, et al. TAS2R activation promotes airway smooth muscle relaxation despite β2-adrenergic receptor tachyphylaxis. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2012;303(4):L304-LL11
  49. 49. Shaik FA, Singh N, Arakawa M, Duan K, Bhullar RP, Chelikani P. Bitter taste receptors: Extraoral roles in pathophysiology. The International Journal of Biochemistry & Cell Biology. 2016;77:197-204
  50. 50. Claar D, Hartert TV, Peebles RS Jr. The role of prostaglandins in allergic lung inflammation and asthma. Expert Review of Respiratory Medicine. 2015;9(1):55-72
  51. 51. Aso H, Ito S, Mori A, Suganuma N, Morioka M, Takahara N, et al. Differential regulation of airway smooth muscle cell migration by E-prostanoid receptor subtypes. American Journal of Respiratory Cell and Molecular Biology. 2013;48(3):322-329
  52. 52. Kumawat K, Menzen MH, Bos IST, Baarsma HA, Borger P, Roth M, et al. Noncanonical WNT-5A signaling regulates TGF-β-induced extracellular matrix production by airway smooth muscle cells. The FASEB Journal. 2013;27(4):1631-1643
  53. 53. Zemans RL, McClendon J, Aschner Y, Briones N, Young SK, Lau LF, et al. Role of β-catenin-regulated CCN matricellular proteins in epithelial repair after inflammatory lung injury. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2013;304(6):L415-LL27
  54. 54. Song T, Zheng Y-M, Vincent PA, Cai D, Rosenberg P, Wang Y-X. Canonical transient receptor potential 3 channels activate NF-κB to mediate allergic airway disease via PKC-α/IκB-α and calcineurin/IκB-β pathways. The FASEB Journal. 2015;30(1):214-229
  55. 55. Maher SA, Dubuis ED, Belvisi MG. G-protein coupled receptors regulating cough. Current Opinion in Pharmacology. 2011;11(3):248-253
  56. 56. Jha A, Sharma P, Anaparti V, Ryu MH, Halayko AJ. A role for transient receptor potential ankyrin 1 cation channel (TRPA1) in airway hyper-responsiveness? Canadian Journal of Physiology and Pharmacology. 2015;93(3):171-176
  57. 57. Watanabe N, Horie S, Spina D, Michael GJ, Page CP, Priestley JV. Immunohistochemical localization of transient receptor potential vanilloid subtype 1 in the trachea of ovalbumin-sensitized Guinea pigs. International Archives of Allergy and Immunology. 2008;146(Suppl. 1):28-32
  58. 58. McAlexander MA, Luttmann MA, Hunsberger GE, Undem BJ. Transient receptor potential vanilloid 4 activation constricts the human bronchus via the release of cysteinyl leukotrienes. Journal of Pharmacology and Experimental Therapeutics. 2014;349(1):118-125
  59. 59. Zhao L, Sullivan MN, Chase M, Gonzales AL, Earley S. Calcineurin/nuclear factor of activated T cells-coupled vanilliod transient receptor potential channel 4 Ca2+ sparklets stimulate airway smooth muscle cell proliferation. American Journal of Respiratory Cell and Molecular Biology. 2014;50(6):1064-1075
  60. 60. Nassini R, Pedretti P, Moretto N, Fusi C, Carnini C, Facchinetti F, et al. Transient receptor potential ankyrin 1 channel localized to non-neuronal airway cells promotes non-neurogenic inflammation. PLoS One. 2012;7(8):e42454
  61. 61. Zhang L, An X, Wang Q , He M. Activation of cold-sensitive channels TRPM8 and TRPA1 inhibits the proliferative airway smooth muscle cell phenotype. Lung. 2016;194(4):595-603
  62. 62. L-m Z, Kuang H-y, L-x Z, Wu J-z, X-l C, X-y Z, et al. Effect of TRPV1 channel on proliferation and apoptosis of airway smooth muscle cells of rats. Journal of Huazhong University of Science and Technology. Medical Sciences. 2014;34(4):504-509
  63. 63. Takahara N, Ito S, Furuya K, Naruse K, Aso H, Kondo M, et al. Real-time imaging of ATP release induced by mechanical stretch in human airway smooth muscle cells. American Journal of Respiratory Cell and Molecular Biology. 2014;51(6):772-782
  64. 64. Siddiqui S, Novali M, Tsuchiya K, Hirota N, Geller BJ, McGovern TK, et al. The modulation of large airway smooth muscle phenotype and effects of epidermal growth factor receptor inhibition in the repeatedly allergen-challenged rat. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2013;304(12):L853-LL62
  65. 65. Lauer ME, Cheng G, Swaidani S, Aronica MA, Weigel PH, Hascall VC. Tumor necrosis factor-stimulated gene-6 (TSG-6) amplifies hyaluronan synthesis by airway smooth muscle cells. Journal of Biological Chemistry. 2013;288(1):423-431
  66. 66. Garantziotis S, Brezina M, Castelnuovo P, Drago L. The role of hyaluronan in the pathobiology and treatment of respiratory disease. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2016;310(9):L785-LL95
  67. 67. Darby PJ, Kwan C, Daniel EE. Caveolae from canine airway smooth muscle contain the necessary components for a role in Ca2+ handling. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2000;279(6):L1226-L1L35
  68. 68. Prakash Y, Thompson MA, Vaa B, Matabdin I, Peterson TE, He T, et al. Caveolins and intracellular calcium regulation in human airway smooth muscle. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2007;293(5):L1118-L1L26
  69. 69. Sathish V, Abcejo AJ, VanOosten SK, Thompson MA, Prakash Y, Pabelick CM. Caveolin-1 in cytokine-induced enhancement of intracellular Ca2+ in human airway smooth muscle. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2011;301(4):L607-LL14
  70. 70. Gosens R, Stelmack GL, Bos ST, Dueck G, Mutawe MM, Schaafsma D, et al. Caveolin-1 is required for contractile phenotype expression by airway smooth muscle cells. Journal of Cellular and Molecular Medicine. 2011;15(11):2430-2442
  71. 71. Benayoun L, Druilhe A, Dombret M-C, Aubier M, Pretolani M. Airway structural alterations selectively associated with severe asthma. American Journal of Respiratory and Critical Care Medicine. 2003;167(10):1360-1368
  72. 72. Shiomi T, Tschumperlin DJ, Park J-A, Sunnarborg SW, Horiuchi K, Blobel CP, et al. TNF-α-converting enzyme/a disintegrin and metalloprotease-17 mediates mechanotransduction in murine tracheal epithelial cells. American Journal of Respiratory Cell and Molecular Biology. 2011;45(2):376-385
  73. 73. Kwak HJ, Park DW, Seo J-Y, Moon J-Y, Kim TH, Sohn JW, et al. The Wnt/β-catenin signaling pathway regulates the development of airway remodeling in patients with asthma. Experimental & Molecular Medicine. 2015;47(12):e198
  74. 74. Zhou L, Goldsmith AM, Bentley JK, Jia Y, Rodriguez ML, Abe MK, et al. 4E-binding protein phosphorylation and eukaryotic initiation factor-4E release are required for airway smooth muscle hypertrophy. American Journal of Respiratory Cell and Molecular Biology. 2005;33(2):195-202
  75. 75. Trian T, Benard G, Begueret H, Rossignol R, Girodet P-O, Ghosh D, et al. Bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma. Journal of Experimental Medicine. 2007;204(13):3173-3181
  76. 76. Pieper M, Chaudhary N, Park J. Acetylcholine-induced proliferation of fibroblasts and myofibroblasts in vitro is inhibited by tiotropium bromide. Life Sciences. 2007;80(24-25):2270-2273
  77. 77. Dekkers BG, Maarsingh H, Meurs H, Gosens R. Airway structural components drive airway smooth muscle remodeling in asthma. Proceedings of the American Thoracic Society. 2009;6(8):683-692
  78. 78. Simeone-Penney MC, Severgnini M, Rozo L, Takahashi S, Cochran BH, Simon AR. PDGF-induced human airway smooth muscle cell proliferation requires STAT3 and the small GTPase Rac1. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2008;294(4):L698-L704
  79. 79. Townsend EA, Miller VM, Prakash Y. Sex differences and sex steroids in lung health and disease. Endocrine Reviews. 2012;33(1):1-47
  80. 80. Larner-Svensson HM, Williams AE, Tsitsiou E, Perry MM, Jiang X, Chung KF, et al. Pharmacological studies of the mechanism and function of interleukin-1β-induced miRNA-146a expression in primary human airway smooth muscle. Respiratory Research. 2010;11(1):68
  81. 81. Schuliga M, Ong SC, Soon L, Zal F, Harris T, Stewart AG. Airway smooth muscle remodels pericellular collagen fibrils: Implications for proliferation. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2010;298(4):L584-LL92
  82. 82. Billington CK, Ojo OO, Penn RB, Ito S. cAMP regulation of airway smooth muscle function. Pulmonary Pharmacology & Therapeutics. 2013;26(1):112-120
  83. 83. Donovan C, Tan X, Bourke JE. PPARγ ligands regulate noncontractile and contractile functions of airway smooth muscle: Implications for asthma therapy. PPAR Research. 2012;2012:809164
  84. 84. Halwani R, Al-Abri J, Beland M, Al-Jahdali H, Halayko AJ, Lee TH, et al. CC and CXC chemokines induce airway smooth muscle proliferation and survival. The Journal of Immunology. 2011:1001210
  85. 85. Ghavami S, Mutawe MM, Schaafsma D, Yeganeh B, Unruh H, Klonisch T, et al. Geranylgeranyl transferase 1 modulates autophagy and apoptosis in human airway smooth muscle. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2011;302(4):L420-L4L8
  86. 86. Fogli S, Stefanelli F, Picchianti L, Del Re M, Mey V, Bardelli C, et al. Synergistic interaction between PPAR ligands and salbutamol on human bronchial smooth muscle cell proliferation. British Journal of Pharmacology. 2013;168(1):266-275
  87. 87. Folinsbee LJ. Human health effects of exposure to airborne acid. Environmental Health Perspectives. 1989;79:195
  88. 88. Jyothula SS, Eissa NT. Autophagy and role in asthma. Current Opinion in Pulmonary Medicine. 2013;19(1):30-35
  89. 89. Poon A, Eidelman D, Laprise C, Hamid Q. ATG5, autophagy and lung function in asthma. Autophagy. 2012;8(4):694-695
  90. 90. Williams AE, Larner-Svensson H, Perry MM, Campbell GA, Herrick SE, Adcock IM, et al. MicroRNA expression profiling in mild asthmatic human airways and effect of corticosteroid therapy. PLoS One. 2009;4(6):e5889
  91. 91. Comer BS, Camoretti-Mercado B, Kogut PC, Halayko AJ, Solway J, Gerthoffer WT. MicroRNA-146a and microRNA-146b expression and anti-inflammatory function in human airway smooth muscle. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2014;307(9):L727-LL34
  92. 92. Jude JA, Dileepan M, Subramanian S, Solway J, Panettieri RA Jr, Walseth TF, et al. miR-140-3p regulation of TNF-α-induced CD38 expression in human airway smooth muscle cells. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2012;303(5):L460-L4L8
  93. 93. Deshpande D, Dileepan M, Walseth T, Subramanian S, Kannan M. MicroRNA regulation of airway inflammation and airway smooth muscle function: Relevance to asthma. Drug Development Research. 2015;76(6):286-295
  94. 94. Dileepan M, Jude JA, Rao SP, Walseth TF, Panettieri RA, Subramanian S, et al. MicroRNA-708 regulates CD38 expression through signaling pathways JNK MAP kinase and PTEN/AKT in human airway smooth muscle cells. Respiratory Research. 2014;15(1):107
  95. 95. Guedes AG, Deshpande DA, Dileepan M, Walseth TF, Panettieri RA Jr, Subramanian S, et al. CD38 and airway hyper-responsiveness: Studies on human airway smooth muscle cells and mouse models. Canadian Journal of Physiology and Pharmacology. 2014;93(2):145-153
  96. 96. Mohamed JS, Hajira A, Li Z, Paulin D, Boriek AM. Desmin regulates airway smooth muscle hypertrophy through early growth-responsive protein-1 and microRNA-26a. Journal of Biological Chemistry. 2011;286(50):43394-43404
  97. 97. Hu R, Pan W, Fedulov AV, Jester W, Jones MR, Weiss ST, et al. MicroRNA-10a controls airway smooth muscle cell proliferation via direct targeting of the PI3 kinase pathway. The FASEB Journal. 2014;28(5):2347-2357
  98. 98. Chen M, Huang L, Zhang W, Shi J, Lin X, Lv Z, et al. MiR-23b controls TGF-β1 induced airway smooth muscle cell proliferation via TGFβR2/p-Smad3 signals. Molecular Immunology. 2016;70:84-93
  99. 99. Liu Y, Yang K, Sun X, Fang P, Shi H, Xu J, et al. MiR-138 suppresses airway smooth muscle cell proliferation through the PI3K/AKT signaling pathway by targeting PDK1. Experimental Lung Research. 2015;41(7):363-369
  100. 100. Liu Y, Sun X, Wu Y, Fang P, Shi H, Xu J, et al. Effects of miRNA-145 on airway smooth muscle cells function. Molecular and Cellular Biochemistry. 2015;409(1-2):135-143
  101. 101. Liao G, Panettieri RA, Tang DD. MicroRNA-203 negatively regulates c-Abl, ERK1/2 phosphorylation, and proliferation in smooth muscle cells. Physiological Reports. 2015;3(9):e12541
  102. 102. Aravamudan B, Thompson MA, Pabelick CM, Prakash Y. Mitochondria in lung diseases. Expert Review of Respiratory Medicine. 2013;7(6):631-646
  103. 103. Contreras L, Drago I, Zampese E, Pozzan T. Mitochondria: The calcium connection. Biochimica et Biophysica Acta (BBA) - Bioenergetics. 2010;1797(6-7):607-618
  104. 104. Rizzuto R, De Stefani D, Raffaello A, Mammucari C. Mitochondria as sensors and regulators of calcium signalling. Nature Reviews Molecular Cell Biology. 2012;13(9):566
  105. 105. Girodet P-O, Allard B, Thumerel M, Begueret H, Dupin I, Ousova O, et al. Bronchial smooth muscle remodeling in nonsevere asthma. American Journal of Respiratory and Critical Care Medicine. 2016;193(6):627-633
  106. 106. Chen T, Zhu L, Wang T, Ye H, Huang K, Hu Q. Mitochondria depletion abolishes agonist-induced Ca2+ plateau in airway smooth muscle cells: Potential role of H2O2. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2009;298(2):L178-LL88
  107. 107. Michaeloudes C, Sukkar MB, Khorasani NM, Bhavsar PK, Chung KF. TGF-β regulates Nox4, MnSOD and catalase expression, and IL-6 release in airway smooth muscle cells. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2010;300(2):L295-L304
  108. 108. Delmotte P, Sieck GC. Interaction between endoplasmic/sarcoplasmic reticulum stress (ER/SR stress), mitochondrial signaling and Ca2+ regulation in airway smooth muscle (ASM). Canadian Journal of Physiology and Pharmacology. 2014;93(2):97-110
  109. 109. Guo Q, Li H, Liu J, Xu L, Yang L, Sun Z, et al. Tunicamycin aggravates endoplasmic reticulum stress and airway inflammation via PERK-ATF4-CHOP signaling in a murine model of neutrophilic asthma. Journal of Asthma. 2017;54(2):125-133
  110. 110. Hsu KJ, Turvey SE. Functional analysis of the impact of ORMDL3 expression on inflammation and activation of the unfolded protein response in human airway epithelial cells. Allergy, Asthma & Clinical Immunology. 2013;9(1):4

Written By

Wenchao Tang

Submitted: October 15th, 2018 Reviewed: January 13th, 2019 Published: February 13th, 2019