Airway Smooth Muscle Remodeling Research Articles

Expression of Semaphorin3E/PlexinD1 in Human airway smooth muscle cells of COPD patients.

Semaphorin-3E (sema3E) is a member of axon guidance proteins that have emerged recently as essential regulators of cell migration and proliferation. It binds to plexinD1 with high affinity and is expressed in different cell types, including immune, cancer, and epithelial cells. Recent work in our lab has revealed a critical immunoregulatory role of sema3E in experimental allergic asthma; however, its role in COPD remains unclear. This study aimed to investigate the expression of sema3E and its receptor, plexinD1, in the airways of COPD patients and whether sema3E regulates airway smooth muscle (ASM) cell proliferation, a key feature of airway remodelling in COPD. We first demonstrate that human ASM cells obtained from COPD express sema3E and plexinD1 at both mRNA and protein levels. Also, bronchial sections from COPD patients displayed immunoreactivity of sema3E and its receptor plexinD1, suggestive of functional contribution of sema3E in airway remodeling. In contrast to ASM cells from healthy donors, sema3E did not inhibit the platelet-derived growth factor (PDGF) induced cell proliferation in ASM cells of COPD patients that were consistent with the binding of endogenous sema3E to its receptors on the cell surface and the expression and release of p61KDa-sema3E isoform. Our results support the sema3E-plexinD1 axis involvement in COPD airway smooth muscle remodelling.

PM2.5 exposure-induced senescence-associated secretory phenotype in airway smooth muscle cells contributes to airway remodeling

Fine particulate matter (PM2.5) has been linked to increased severity and incidence of airway diseases, especially chronic obstructive pulmonary disease (COPD) and asthma. Airway remodeling is an important event in both COPD and asthma, and airway smooth muscle cells (ASMCs) are key cells which directly involved in airway remodeling. However, it was unclear how PM2.5 affected ASMCs. This study investigates the effects of PM2.5 on airway smooth muscle and its mechanism. We first showed that inhaled particulate matter was distributed in the airway smooth muscle bundle, combined with increased airway smooth muscle bundle and collagen deposition in vivo. Then, we demonstrated that PM2.5 induced up-regulation of collagen-I and alpha-smooth muscle actin (α-SMA) expression in rat and human ASMCs in vitro. Next, we found PM2.5 led to rat and human ASMCs senescence and exhibited senescence-associated secretory phenotype (SASP) by autophagy-induced GATA4/TRAF6/NF-κB signaling, which contributed to collagen-I and α-SMA synthesis as well as airway smooth muscle remodeling. Together, our results provided evidence that SASP induced by PM2.5 in airway smooth muscle cells prompted airway remodeling.

CD4+ T cell-derived IFN-γ and LIGHT synergistically upregulate chemokine production from airway smooth muscle cells.

Airway smooth muscle (ASM) remodeling in asthmatic airways may contribute to persistent airflow limitation and airway hyperresponsiveness. CD4+ T cells infiltrate the ASM layer where they may induce a proliferative and secretory ASM cell phenotype. We studied the interaction between activated CD4+ T cells and ASM cells in co-culture invitro and investigated the effects of CD4+ T cells on chemokine production by ASM cells. CD4+ T cells induced marked upregulation of C-X-C motif chemokine ligands (CXCL) 9, 10, and 11 in ASM cells. Blockade of the IFN-γ receptor on ASM cells prevented this upregulation. Furthermore, T cell-derived IFN-γ and LIGHT (lymphotoxin, exhibits inducible expression and competes with HSV glycoprotein D for binding to herpesvirus entry mediator, a receptor expressed on T lymphocytes) synergize in a dose-dependent manner to coordinately enhance CXCL9, 10, and 11 expression. The synergistic property of LIGHT was mediated exclusively through the lymphotoxin-β receptor (LTBR), but not herpes virus entry mediator (HVEM). Disruption of LTBR signaling in ASM cells reduced CXCL9, 10, and 11 production and ASM cell-mediated CD4+ T cell chemotaxis. We conclude that the LIGHT-LTBR signaling axis acts together with IFN-γ to regulate chemokines that mediate lymphocyte infiltration in asthmatics.

Severe asthma in horses is associated with increased airway innervation.

Altered innervation structure and function contribute to airway hyperresponsiveness in human asthma, yet the role of innervation in airflow limitation in asthma in horses remains unknown. To characterize peribronchial innervation in horses with asthma. We hypothesized that airway innervation increases in horses with asthma compared with controls. Formalin-fixed lung samples from 8 horses with severe asthma and 8 healthy horses from the Equine Respiratory Tissue Biobank. Ante-mortem lung function was recorded. Blinded case-control study. Immunohistochemistry was performed using rabbit anti-s100 antibody as a neuronal marker for myelinating and non-myelinating Schwann cells. The number and cumulative area of nerves in the peribronchial region and associated with airway smooth muscle were recorded using histomorphometry and corrected for airway size. Both the number (median [IQR]: 1.87 × 10-5 nerves/μm2 [1.28 × 10-5 ]) and the cumulative nerve area (CNA; 1.03 × 10-3 CNA/μm2 [1.57 × 10-3 ]) were higher in the peribronchial region of horses with asthma compared with controls (5.17 × 10-6 nerves/μm2 [3.76 × 10-6 ], 4.14 × 10-4 CNA/μm2 [2.54 × 10-4 ], Mann-Whitney, P = .01). The number of nerves within or lining airway smooth muscle was significantly higher in horses with asthma (4.47 × 10-6 nerves/μm2 [5.75 × 10-6 ]) compared with controls (2.26 × 10-6 nerves/μm2 [1.16 × 10-6 ], Mann-Whitney, P = .03). Asthma in horses is associated with greater airway innervation, possibly contributing to airway smooth muscle remodeling and exacerbating severity of the disease.

S100A alarmins and thymic stromal lymphopoietin (TSLP) regulation in severe asthma following bronchial thermoplasty

RationaleSevere asthma affects a small proportion of asthmatics but represents a significant healthcare challenge. Bronchial thermoplasty (BT) is an interventional treatment approach preconized for uncontrolled severe asthma after considering biologics therapy. It was showed that BT long-lastingly improves asthma control. These improvements seem to be related to the ability of BT to reduce airway smooth muscle remodeling, reduce the number of nerve fibers and to modulate bronchial epithelium integrity and behavior. Current evidence suggest that BT downregulates epithelial mucins expression, cytokine production and metabolic profile. Despite these observations, biological mechanisms explaining asthma control improvement post-BT are still not well understood.ObjectivesTo assess whether BT affects gene signatures in bronchial epithelial cells (BECs).MethodsIn this study we evaluated the transcriptome of cultured bronchial epithelial cells (BECs) of severe asthmatics obtained pre- and post-BT treatment using microarrays. We further validated gene and protein expressions in BECs and in bronchial biopsies with immunohistochemistry pre- and post-BT treatment.Measurements and main resultsTranscriptomics analysis revealed that a large portion of differentially expressed genes (DEG) was involved in anti-viral response, anti-microbial response and pathogen induced cytokine storm signaling pathway. S100A gene family stood out as five members of this family where consistently downregulated post-BT. Further validation revealed that S100A7, S100A8, S100A9 and their receptor (RAGE, TLR4, CD36) expressions were highly enriched in severe asthmatic BECs. Further, these S100A family members were downregulated at the gene and protein levels in BECs and in bronchial biopsies of severe asthmatics post-BT. TLR4 and CD36 protein expression were also reduced in BECs post-BT. Thymic stromal lymphopoietin (TSLP) and human β-defensin 2 (hBD2) were significantly decreased while no significant change was observed in IL-25 and IL-33.ConclusionsThese data suggest that BT might improve asthma control by downregulating epithelial derived S100A family expression and related downstream signaling pathways.

Polyphyllin VII alleviates pulmonary hypertension by inducing miR-205–5p to target the β-catenin pathway

ObjectiveThis study aims to investigate the impact of Polyphyllin VII (PP7) on pulmonary hypertension (PH) and elucidate the underlying mechanism involving microRNA (miR)−205–5p/β-catenin. MethodsThe PH rat model was induced through hypoxia exposure. The effects of intraperitoneal injection of PP7 on pulmonary artery tissue pathology, hemodynamics, miR-205–5p expression and β-catenin protein levels were assessed. In vitro, pulmonary arterial smooth muscle cells (PASMCs) were subjected to hypoxic conditions. Moreover, miR-205–5p and/or β-catenin were overexpressed through transfection. PASMCs were pre-cultured in 20 μM PP7, and subsequent measurements included proliferation, apoptosis and vascular remodeling protein expression. ResultsPP7 ameliorated PH symptoms in rats, upregulated miR-205–5p expression and inhibited β-catenin protein expression. Furthermore, miR-205–5p upregulation inhibited β-catenin expression in PASMCs. The overexpression of β-catenin aggravated hypoxia-induced proliferation, inhibited apoptosis and further augmented VEGF and α-SMA protein expression. Additionally, miR-205–5p overexpression alleviated the hypoxia-induced PASMC proliferation and apoptosis by inhibiting β-catenin protein expression. Under hypoxic conditions, PP7 significantly elevated miR-205–5p while downregulating β-catenin protein expression. Furthermore, inhibiting miR-205–5p counteracted the inhibitory effect of PP7 on β-catenin, consequently blocking the regulatory role of PP7 in PASMC proliferation and apoptosis. ConclusionPP7 likely modulates β-catenin protein levels by promoting miR-205–5p expression, thereby alleviating PH, vascular remodeling and airway smooth muscle remodeling.

The biased M3 mAChR ligand PD 102807 mediates qualitatively distinct signaling to regulate airway smooth muscle phenotype

Airway smooth muscle (ASM) cells attain a hypercontractile phenotype during obstructive airway diseases. We recently identified a biased M3 muscarinic acetylcholine receptor (mAChR) ligand, PD 102807, that induces GRK-/arrestin-dependent AMP-activated protein kinase (AMPK) activation to inhibit transforming growth factor-β-induced hypercontractile ASM phenotype. Conversely, the balanced mAChR agonist, methacholine (MCh), activates AMPK yet does not regulate ASM phenotype. In the current study, we demonstrate that PD 102807- and MCh-induced AMPK activation both depend on Ca2+/calmodulin-dependent kinase kinases (CaMKKs). However, MCh-induced AMPK activation is calcium-dependent and mediated by CaMKK1 and CaMKK2 isoforms. In contrast, PD 102807-induced signaling is calcium-independent and mediated by the atypical subtype protein kinase C-iota and the CaMKK1 (but not CaMKK2) isoform. Both MCh- and PD 102807-induced AMPK activation involve the AMPK α1 isoform. PD 102807-induced AMPK α1 (but not AMPK α2) isoform activation mediates inhibition of the mammalian target of rapamycin complex 1 (mTORC1) in ASM cells, as demonstrated by increased Raptor (regulatory-associated protein of mTOR) phosphorylation as well as inhibition of phospho-S6 protein and serum response element-luciferase activity. The mTORC1 inhibitor rapamycin and the AMPK activator metformin both mimic the ability of PD 102807 to attenuate transforming growth factor-β-induced α-smooth muscle actin expression (a marker of hypercontractile ASM). These data indicate that PD 102807 transduces a signaling pathway (AMPK-mediated mTORC1 inhibition) qualitatively distinct from canonical M3 mAChR signaling to prevent pathogenic remodeling of ASM, thus demonstrating PD 102807 is a biased M3 mAChR ligand with therapeutic potential for the management of obstructive airway disease.

The Role of Vitamin D Supplementation on Airway Remodeling in Asthma: A Systematic Review.

Asthma is a common chronic respiratory disease that affects millions of people worldwide, and its prevalence continues to increase. Vitamin D has been proposed as a potential environmental factor in asthma pathogenesis, due to its immunomodulatory effects. This systematic review aimed to evaluate the effect of vitamin D supplementation in order to prevent airway remodeling in asthmatic patients. Four electronic databases, namely PubMed, Embase, Clinical trails.gov, and CINAHL, were thoroughly searched to conduct a comprehensive literature review. The International Prospective Register of Systematic Reviews (CRD42023413798) contains a record of the registered protocol. We identified 9447 studies during the initial search; 9 studies (0.1%) met the inclusion criteria and were included in the systematic review. All included studies were experimental studies that investigated the impact of vitamin D supplementation on airway remodeling in asthma. The studies included in this review suggest that vitamin D inhibits airway smooth muscle cell contraction and remodeling, reduces inflammation, regulates collagen synthesis in the airways, and modulates the action of bronchial fibroblasts. However, one study suggests that TGF-β1 can impair vitamin D-induced and constitutive airway epithelial host defense mechanisms. Overall, vitamin D appears to have a potential role in the prevention and management of asthma.

Quantifying airway remodelling for research or clinical purposes: How should we normalize for airway size?

Quantifying airway remodelling for research or clinical purposes: How should we normalize for airway size?

Myocd regulates airway smooth muscle cell remodeling in response to chronic asthmatic injury.

Abnormal growth of airway smooth muscle cells is one of the key features in asthmatic airway remodeling, which is associated with asthma severity. The mechanisms underlying inappropriate airway smooth muscle cell growth in asthma remain largely unknown. Myocd has been reported to act as a key transcriptional coactivator in promoting airway-specific smooth muscle development in fetal lungs. Whether Myocd controls airway smooth muscle remodeling in asthma has not been investigated. Mice with lung mesenchyme-specific deletion of Myocd after lung development were generated, and a chronic asthma model was established by sensitizing and challenging the mice with ovalbumin for a prolonged period. Comparison of the asthmatic pathology between the Myocd knockout mice and the wild-type controls revealed that abrogation of Myocd mitigated airway smooth muscle cell hypertrophy and hyperplasia, accompanied by reduced peri-airway inflammation, decreased fibrillar collagen deposition on airway walls, and attenuation of abnormal mucin production in airway epithelial cells. Our study indicates that Myocd is a key transcriptional coactivator involved in asthma airway remodeling. Inhibition of Myocd in asthmatic airways may be an effective approach to breaking the vicious cycle of asthmatic progression, providing a novel strategy in treating severe and persistent asthma. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Heterogeneity of Airway Smooth Muscle Remodeling in Asthma.

Rationale: Ventilatory defects in asthma are heterogeneous and may represent the distribution of airway smooth muscle (ASM) remodeling. Objectives: To determine the distribution of ASM remodeling in mild-severe asthma. Methods: The ASM area was measured in nine airway levels in three bronchial pathways in cases of nonfatal (n = 30) and fatal asthma (n = 20) and compared with control cases without asthma (n = 30). Correlations of ASM area within and between bronchial pathways were calculated. Asthma cases with 12 large and 12 small airways available (n = 42) were classified on the basis of the presence or absence of ASM remodeling (more than two SD of mean ASM area of control cases, n = 86) in the large or small airway or both. Measurements and Main Results: ASM remodeling varied widely within and between cases of nonfatal asthma and was more widespread and confluent and more marked in fatal cases. There were weak correlations of ASM between levels within the same or separate bronchial pathways; however, predictable patterns of remodeling were not observed. Using mean data, 44% of all asthma cases were classified as having no ASM remodeling in either the large or small airway despite a three- to 10-fold increase in the number of airways with ASM remodeling and 81% of asthma cases having ASM remodeling in at least one large and small airway. Conclusions: ASM remodeling is related to asthma severity but is heterogeneous within and between individuals and may contribute to the heterogeneous functional defects observed in asthma. These findings support the need for patient-specific targeting of ASM remodeling.

Asthma and Vitamin D Deficiency: Occurrence, Immune Mechanisms, and New Perspectives.

Asthma, as a chronic inflammatory condition of the airways, has a considerable prevalence among children. Vitamin D might play a role in asthma pathogenesis by affecting the development of the lung, regulating the immune responses, and remodeling of airway smooth muscle (ASM). Study results on the association between the serum level of vitamin D and asthma severity have suggested a converse relationship between lower vitamin D levels and more severe clinical courses. However, they are not consistent in these findings and have shown insignificant correlations, as well. The possible effects of vitamin D on asthma have led researchers to consider this vitamin a potential prophylactic and therapeutic tool for managing children with variant degrees of asthma. Adding vitamin D to the routine corticosteroid therapy of asthmatic children is another field of interest that has shown promising results. In this narrative review study, we aim to elaborate on the existing knowledge on the role of vitamin D in asthma pathogenesis and prognosis, explain the controversies that exist on the effectiveness of treating patients with vitamin D supplements, and make a general conclusion about how vitamin D actually is linked to asthma in children.

STIM1 is the key that unlocks airway smooth muscle remodeling and hyperresponsiveness during asthma

Airway smooth muscle remodeling and hyperresponsiveness are critical determinants of asthma severity, but the precise mechanisms regulating these disease processes remain elusive. In their latest study published in PNAS, Trebak and colleagues demonstrate that STIM1 (stromal-interacting molecule 1) expression is upregulated in airway smooth muscle cells during asthma and facilitates Ca2+ influx to drive airway remodeling and hyperresponsiveness.

LIGHT - LTßR Signaling is Essential for Airway Smooth Muscle Remodeling and Asthmatic Airway Hyperresponsiveness

Airway hyperresponsiveness (AHR) and dysregulation of airway smooth muscle cells (ASM) is central to the severity of asthma. However which molecules control ASM in asthmatics is still largely unclear. High levels of the cytokine TNFSF14/LIGHT have been linked to asthma severity and lower baseline FEV1 %predicted, implying signals through either of its receptors, LTbR and HVEM, could directly control ASM dysfunction. We aimed to determine whether signaling via LTbR or HVEM from LIGHT controls ASM hyperreactivity.

Pulmonary functional MRI: Detecting the structure-function pathologies that drive asthma symptoms and quality of life.

Pulmonary functional MRI (PfMRI) using inhaled hyperpolarized, radiation-free gases (such as 3 He and 129 Xe) provides a way to directly visualize inhaled gas distribution and ventilation defects (or ventilation heterogeneity) in real time with high spatial (~mm3 ) resolution. Both gases enable quantitative measurement of terminal airway morphology, while 129 Xe uniquely enables imaging the transfer of inhaled gas across the alveolar-capillary tissue barrier to the red blood cells. In patients with asthma, PfMRI abnormalities have been shown to reflect airway smooth muscle dysfunction, airway inflammation and remodelling, luminal occlusions and airway pruning. The method is rapid (8-15 s), cost-effective (~$300/scan) and very well tolerated in patients, even in those who are very young or very ill, because unlike computed tomography (CT), positron emission tomography and single-photon emission CT, there is no ionizing radiation and the examination takes only a few seconds. However, PfMRI is not without limitations, which include the requirement of complex image analysis, specialized equipment and additional training and quality control. We provide an overview of the three main applications of hyperpolarized noble gas MRI in asthma research including: (1) inhaled gas distribution or ventilation imaging, (2) alveolar microstructure and finally (3) gas transfer into the alveolar-capillary tissue space and from the tissue barrier into red blood cells in the pulmonary microvasculature. We highlight the evidence that supports a deeper understanding of the mechanisms of asthma worsening over time and the pathologies responsible for symptoms and disease control. We conclude with a summary of approaches that have the potential for integration into clinical workflows and that may be used to guide personalized treatment planning.

STIM1 is a core trigger of airway smooth muscle remodeling and hyperresponsiveness in asthma

Airway remodeling and airway hyperresponsiveness are central drivers of asthma severity. Airway remodeling is a structural change involving the dedifferentiation of airway smooth muscle (ASM) cells from a quiescent to a proliferative and secretory phenotype. Here, we show up-regulation of the endoplasmic reticulum Ca2+ sensor stromal-interacting molecule 1 (STIM1) in ASM of asthmatic mice. STIM1 is required for metabolic and transcriptional reprogramming that supports airway remodeling, including ASM proliferation, migration, secretion of cytokines and extracellular matrix, enhanced mitochondrial mass, and increased oxidative phosphorylation and glycolytic flux. Mechanistically, STIM1-mediated Ca2+ influx is critical for the activation of nuclear factor of activated T cells 4 and subsequent interleukin-6 secretion and transcription of pro-remodeling transcription factors, growth factors, surface receptors, and asthma-associated proteins. STIM1 drives airway hyperresponsiveness in asthmatic mice through enhanced frequency and amplitude of ASM cytosolic Ca2+ oscillations. Our data advocates for ASM STIM1 as a target for asthma therapy.

Plk1 Regulates Caspase-9 Phosphorylation at Ser-196 and Apoptosis of Human Airway Smooth Muscle Cells.

Airway smooth muscle thickening, a key characteristic of chronic asthma, is largely attributed to increased smooth muscle cell proliferation and reduced smooth muscle apoptosis. Polo-like kinase 1 (Plk1) is a serine/threonine protein kinase that participates in the pathogenesis of airway smooth muscle remodeling. Although the role of Plk1 in cell proliferation and migration is recognized, its function in smooth muscle apoptosis has not been previously investigated. Caspase-9 (Casp9) is a key enzyme that participates in the execution of apoptosis. Casp9 phosphorylation at Ser-196 and Thr-125 is implicated in regulating its activity in cancer cells and epithelial cells. Here, exposure of human airway smooth muscle (HASM) cells to platelet-derived growth factorfor 24 hours enhanced the expression of Plk1 and Casp9 phosphorylation at Ser-196, but not Thr-125. Overexpression of Plk1 in HASM cells increased Casp9 phosphorylation at Ser-196. Moreover, the expression of Plk1 increased the levels of pro-Casp9 and pro-Casp3 and inhibited apoptosis, demonstrating a role of Plk1 in inhibiting apoptosis. Knockdown of Plk1 reduced Casp9 phosphorylation at Ser-196, reduced pro-Casp9/3 expression, and increased apoptosis. Furthermore, Casp9 phosphorylation at Ser-196 was upregulated in asthmatic HASM cells, which was associated with increased Plk1 expression. Knockdown of Plk1 in asthmatic HASM cells decreased Casp9 phosphorylation at Ser-196 and enhanced apoptosis. Together, these studies disclose a previously unknown mechanism that the Plk1-Casp9/3 pathway participates in the controlling of smooth muscle apoptosis.

Airway smooth muscle remodelling in mild and moderate equine asthma

Airway smooth muscle remodelling in severe equine asthma includes both thickening of airway smooth muscle, resulting from hyperplasia and hypertrophy, and changes in contractility. However, airway smooth muscle changes have not been studied in milder forms of the disease. To investigate bronchial smooth muscle remodelling in horses with mild and moderate asthma (MEA). Retrospective case-control study. The endobronchial biopsies from 18 horses with MEA referred to the Equine Hospital of the Université de Montréal and from seven healthy age-matched control horses were studied. The diagnosis was based on clinical signs and bronchoalveolar lavage fluid cytology. Airway smooth muscle cell proliferation was measured by quantifying the expression of the proliferating cell nuclear antigen (PCNA) using immunohistochemistry and histomorphometry. The expression of the (+)insert smooth muscle myosin heavy chain (SMMHC) isoform, an hypercontractile protein, was assessed by RT-qPCR. Expression of the (+)insert SMMHC isoform in airway smooth muscle was approximately 1.5 times greater in horses with MEA compared with controls (P=.02, mean difference 0.01). Although there were no differences between groups in the proliferation of airway smooth muscle cells (P=.4) or myocyte density (P=.3, mean difference -0.6), the percentage of proliferating myocytes was correlated to pulmonary neutrophilia in horses with neutrophilic inflammation (P=.01, r=.80) and to the expression of the (+)insert SMMHC isoform in asthmatic horses (P=.03, r=.66). Small cohorts of horses were studied, and conclusions are limited to the central airways. These results confirm the presence of bronchial smooth muscle remodelling in mild forms of equine asthma and pave the way for the development of biomarkers to measure asthma progression and response to therapy.

Remodeling in equine asthma-Effects of antigen avoidance and pharmacological therapy

The term remodeling describes the process resulting in a tissue that is structurally and architecturally altered compared to its healthy counterpart. At least in severe equine asthma, this occurs mainly, but not exclusively, as a consequence of neutrophilic airway inflammation and is characterized by hypertrophy of the smooth muscle layers in airway and arterial walls as well as fibrosis of the bronchial walls and pulmonary interstitial tissue. To date, much less is known for mild to moderate equine asthma. For a long time it was assumed that these processes are irreversible, and at least for the remodeling of airway smooth muscle this is valid until today. In contrast, remodeling of the extracellular matrix disappears almost completely following long-term remission in consequence to strict antigen avoidance and environmental improvement as well as after glucocorticoid therapy. The remodeling of the arterial vasculature is also reversible following at least 12 months of antigen avoidance and bronchodilatory therapy, but not by inhaled glucocorticoids alone. Although not proven to date, the mild to moderate forms with a good prognosis for complete recovery may be a progenitor for severe equine asthma, in which lung function is restricted even during disease remission despite the absence of obvious clinical signs. Early diagnosis and therapy are, therefore, essential for the management of equine asthma prior to the development of irreversible remodeling, in particular of the bronchial smooth muscle. Antigen avoidance is of highest importance, and should be supported by glucocorticoids and bronchodilators.

Airway Epithelial Cells Drive Airway Smooth Muscle Cell Phenotype Switching to the Proliferative and Pro-inflammatory Phenotype.

The increased mass of airway smooth muscle (ASM) in the airways of asthmatic patients may contribute to the pathology of this disease by increasing the capacity for airway narrowing. Evidence for the airway epithelium as a participant in ASM remodeling is accruing. To investigate mechanisms by which airway epithelial cells induce ASM cell (ASMC) proliferation, we have employed a co-culture model to explore markers of ASMC proliferative phenotype. Co-culture with epithelial cells led to incorporation of bromodeoxyuridine into ASMCs, indicating augmented proliferation and an associated increase in mRNA of the pro-proliferative co-transcription factor Elk1. Although the mitogen heparin-binding epidermal growth factor (HB-EGF) was augmented in the co-culture supernatant, the ASMC epidermal growth factor receptor (EGFR), an effector of HB-EGF induced proliferation, did not mediate epithelial-induced proliferation. The co-culture increased the expression of ASMC mRNA for the pro-inflammatory cytokines IL-6 and IL-8 as well as the pro-proliferative microRNA miR-210. The transcriptional repressor Max-binding protein (Mnt), a putative target of miR-210, was transcriptionally repressed in co-cultured ASMCs. Together, these data indicate that the airway epithelium-induced proliferative phenotype of ASMCs is not driven by EGFR signaling, but rather may be dependent on miR210 targeting of tumor suppressor Mnt.