Airway Remodeling In Allergic Asthma Research Articles

LincR-PPP2R5C Deficiency Alleviates Airway Remodeling by Inhibiting Epithelial-Mesenchymal Transition Through the PP2A/TGF-β1 Signaling Pathway in Chronic Experimental Allergic Asthma.

Airway remodeling is a key characteristic of allergic asthma. Epithelial-mesenchymal transition (EMT) induced by various factors, particularly transforming growth factor (TGF)-β1, orchestrates airway remodeling. Protein phosphatase 2A (PP2A), an important serine-threonine phosphatase, is involved in TGF-β1 production and EMT. Long noncoding RNAs (lncRNAs) have emerged as novel players in regulating EMT. Here, we aimed to explore the effects and mechanisms of action of lincR-PPP2R5C, a lncRNA that affects PP2A activity, on airway remodeling in a mouse model of chronic allergic asthma. LincR-PPP2R5C knockout (KO) alleviated inflammatory responses in house dust mite (HDM)-induced chronic allergic asthma. Moreover, airway remodeling and EMT were reduced in lung tissues of lincR-PPP2R5C KO mice. HDM extract induced EMT in airway epithelial cells, which was decreased following lincR-PPP2R5C KO. Mechanistically, lincR-PPP2R5C deficiency enhanced PP2A activity, which inhibited TGF-β1 production in epithelial cells. In conclusion, lincR-PPP2R5C deficiency prevented HDM-induced airway remodeling in mice by reversing EMT, which was mediated by the PP2A/TGF-β1 signaling pathway. Thus, lncRNAs, i.e., lincR-PPP2R5C, may be potential targets to prevent airway remodeling in allergic asthma.

Angiotensin-(1–7) suppresses airway inflammation and airway remodeling via inhibiting ATG5 in allergic asthma

BackgroundAngiotensin (Ang)-(1–7) can reduce airway inflammation and airway remodeling in allergic asthma. Autophagy-related 5 (ATG5) has attracted wide attentions in asthma. However, the effects of Ang-(1–7) on ATG5-mediated autophagy in allergic asthma are unclear.MethodsIn this study, human bronchial epithelial cell (BEAS-2B) and human bronchial smooth muscle cell (HBSMC) were treated with different dose of Ang-(1–7) to observe changes of cell viability. Changes of ATG5 protein expression were measured in 10 ng/mL of interleukin (IL)-13-treated cells. Transfection of ATG5 small interference RNA (siRNA) or ATG5 cDNA in cells was used to analyze the effects of ATG5 on secretion of cytokines in the IL-13-treated cells. The effects of Ang-(1–7) were compared to the effects of ATG5 siRNA transfection or ATG5 cDNA transfection in the IL-13-treated cells. In wild-type (WT) mice and ATG5 knockout (ATG5−/−) mice, ovalbumin (OVA)-induced airway inflammation, fibrosis and autophagy were observed. In the OVA-induced WT mice, Ang-(1–7) treatment was performed to observe its effects on airway inflammation, fibrosis and autophagy.ResultsThe results showed that ATG5 protein level was decreased with Ang-(1–7) dose administration in the IL-13-treated BEAS-2B and IL13-treated HBSMC. Ang-(1–7) played similar results to ATG5 siRNA that it suppressed the secretion of IL-25 and IL-13 in the IL-13-treated BEAS-2B cells, and inhibited the expression of transforming growth factor (TGF)-β1 and α-smooth muscle actin (α-SMA) protein in the IL-13-treated HBSMC cells. ATG5 cDNA treatment significantly increased the secretion of IL-25 and IL-13 and expression of TGF-β1 and α-SMA protein in IL-13-treated cells. Ang-(1–7) treatment suppressed the effects of ATG5 cDNA in the IL-13-treated cells. In OVA-induced WT mice, Ang-(1–7) treatment suppressed airway inflammation, remodeling and autophagy. ATG5 knockout also suppressed the airway inflammation, remodeling and autophagy.ConclusionsAng-(1–7) treatment suppressed airway inflammation and remodeling in allergic asthma through inhibiting ATG5, providing an underlying mechanism of Ang-(1–7) for allergic asthma treatment.

Proline is increased in allergic asthma and promotes airway remodeling.

Proline and its synthesis enzyme pyrroline-5-carboxylate reductase 1 (PYCR1) are implicated in epithelial-mesenchymal transition (EMT), yet how proline and PYCR1 function in allergic asthmatic airway remodeling via EMT has not yet been addressed to our knowledge. In the present study, increased levels of plasma proline and PYCR1 were observed in patients with asthma. Similarly, proline and PYCR1 in lung tissues were high in a murine allergic asthma model induced by house dust mites (HDMs). Pycr1 knockout decreased proline in lung tissues, with reduced airway remodeling and EMT. Mechanistically, loss of Pycr1 restrained HDM-induced EMT by modulating mitochondrial fission, metabolic reprogramming, and the AKT/mTORC1 and WNT3a/β-catenin signaling pathways in airway epithelial cells. Therapeutic inhibition of PYCR1 in wild-type mice disrupted HDM-induced airway inflammation and remodeling. Deprivation of exogenous proline relieved HDM-induced airway remodeling to some extent. Collectively, this study illuminates that proline and PYCR1 involved with airway remodeling in allergic asthma could be viable targets for asthma treatment.

Ceramide Nanoliposomes as Potential Therapeutic Reagents for Asthma.

Ceramides are an emerging class of anti-inflammatory lipids, and nanoscale ceramide-delivery systems are potential therapeutic strategies for inflammatory diseases. This study investigated the therapeutic effects of ceramide nanoliposomes (CNL) on type 2 inflammation-based asthma, induced by repeated ovalbumin (OVA) challenges. Asthmatic mice intratracheally treated with ceramide-free liposomes (Ghost) displayed typical airway remodeling including mucosal accumulation and subepithelial fibrosis, whereas, in CNL-treated mice, the degree of airway remodeling was significantly decreased. Compared to the Ghost group, CNL treatment unexpectedly failed to significantly influence formation of type 2 cytokines, including IL-5 and IL-13, known to facilitate pathogenic production of airway mucus predominantly comprising MUC5AC mucin. Interestingly, CNL treatment suppressed OVA-evoked hyperplasia of MUC5AC-generating goblet cells in the airways. This suggests that CNL suppressed goblet cell hyperplasia and airway mucosal accumulation independently of type 2 cytokine formation. Mechanistically, CNL treatment suppressed cell growth and EGF-induced activation of Akt, but not ERK1/2, in a human lung epithelial cell culture system recapitulating airway goblet cell hyperplasia. Taken together, CNL is suggested to have therapeutic effects on airway remodeling in allergic asthma by targeting goblet cell hyperplasia. These findings raise the potential of ceramide-based therapies for airway diseases, such as asthma.

Transfer factors peptides (Imuno TF®) modulate the lung inflammation and airway remodeling in allergic asthma.

Allergic asthma is a chronic lung disease in which the lung inflammation and airway remodeling are orchestrated by both the inflammatory and the immune cells that creates a lung millieu that favors the perpetuation of clinical symptoms. The cell signaling in asthma involves the mast cells activation during initial contact with the allergen and, principally, the participation of eosinophils as well as Th2 cells which determine increased levels of IgE, exaggerated secretion of mucus and collagen, and bronchial hyperreactivity. Moreover, allergic asthma presents lower level of cytokines associated to the both Th1 and Treg cells response, and it implies in deficiency of anti-inflammatory response to counterregulate the exaggerated inflammation against allergen. Therefore, the equilibrium between cytokines as well as transcription factors associated to Th2, Th1, and Treg cells is compromised in allergic asthma. Imuno TF® is a food supplement with ability to interfere in immune system pathways. It has been previously demonstrated that Imuno TF® upregulated Th1 cell response whilst downregulated Th2 cell response in human lymphocytes. For this reason, we hypothesized that the Imuno TF effect could be restore the balance between Th1/Th2 CD4 T cells response in murine allergic asthma. Initially, animals were sensitized with OVA via i.p. and challenged with OVA i.n. on days 14, 15 and 16. Treatment with Imuno TF once a day was performed via orogastric from day 17 to day 20. Mice were euthanized on day 21. The Imuno TF reduced eosinophilia, mucus production, and airway remodeling (collagen deposition) in asthma mice. Imuno TF influenced cellular signaling associated to allergic asthma once downregulated STAT6 expression as well as decreased IL-4, IL-5, and IL-13 in lung and serum. In addition, Imuno TF restored T-bet and Foxp3 expression as well as increased IL-12, IFN-ɣ, and IL-10. Ultimately, Imuno TF mitigated the allergic asthma due to the restoration of balance between the responses of Th1/Th2 as well as Treg cells, and their respective transcription factors the T-bet/STAT6 and Foxp3.

House dust mite-induced Akt-ERK1/2-C/EBP beta pathway triggers CCL20-mediated inflammation and epithelial-mesenchymal transition for airway remodeling.

House dust mite (HDM) allergens cause inflammatory responses and chronic allergic diseases such as bronchial asthma and atopic dermatitis. Here, we investigate the mechanism by which HDM induces C-C chemokine ligand 20 (CCL20) expression to promote chronic inflammation and airway remodeling in an HDM-induced bronchial asthma mouse model. We showed that HDM increased CCL20 levels via the Akt-ERK1/2-C/EBPβ pathway. To investigate the role of CCL20 in chronic airway inflammation and remodeling, we made a mouse model of CCL20-induced bronchial asthma. Treatment of anti-CCL20Ab in this mouse model showed the reduced airway hyper-responsiveness and inflammatory cell infiltration into peribronchial region by neutralizing CCL20. In addition, CCL20 induced the Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation through NLRP3 deubiquitination and transcriptional upregulation in BEAS-2B cells. As expected, anti-CCL20Ab markedly suppressed NLRP3 activation induced by CCL20. Moreover, HDM-induced CCL20 leads to epithelial-mesenchymal transition in the lung epithelium which appears to be an important regulator of airway remodeling in allergic asthma. We also found that anti-CCL20Ab attenuates airway inflammation and remodeling in an HDM-induced mouse model of bronchial asthma. Taken together, our results suggest that HDM-induced CCL20 is required for chronic inflammation that contributes airway remodeling in a mouse model of asthma.

The Association Between \u03b2-Dystroglycan in Airway Smooth Muscle and Eosinophils in Allergic Asthma

Allergic asthma (AA) is a complex disorder with heterogeneous features of airway hyperresponsiveness, inflammation, and remodeling. The increase of airway smooth muscle (ASM) mass is a fundamental component of bronchial remodeling in AA, yet the pathophysiological mechanisms and clinical outcomes associated with ASM modulation are still elusive. The objective of this study is to compare the expression level of β-dystroglycan (β-DG) in ASM in AA subjects and a healthy control group and to investigate the relationship between eosinophils and β-DG in ASM in patients with AA. Thirteen AA patients and seven control subjects were analyzed for the ASM area and eosinophil cells. Bronchial biopsies were stained by β-DG and eosinophil cationic protein (ECP) using immunohistochemistry. The proportion of ASM with β-DG staining was greater in those with AA than in the healthy control group (mean (95% CI) (28.3% (23.8–32.7%) vs. 16.4% (14.1–18.5%), P < 0.0001). The number of ECP positive cells was higher in patients with AA than in the control group (4056 (3819–4296) vs. 466 (395–537) cells/mm2P < 0.0001). In AA, the number of ECP positive cells was significantly correlated to the β-DG expression in ASM (r = 0.77, P = 0.002). There is an increased β-DG expression in ASM and a higher number of ECP positive cells in the bronchial biopsy of those with AA than those in the control group. The increased expression of β-DG in ASM in AA subjects correlates with the number of eosinophils, suggesting a role for this cell in airway remodeling in AA.

FoxO1 is a critical regulator of M2-like macrophage activation in allergic asthma.

The pathogenesis of asthma and airway obstruction is the result of an abnormal response to different environmental exposures. The scientific premise of our study was based on the finding that FoxO1 expression is increased in lung macrophages of mice after allergen exposure and human asthmatic patients. Macrophages are capable of switching from one functional phenotype to another, and it is important to understand the mechanisms involved in the transformation of macrophages and how their cellular function affects the peribronchial stromal microenvironment. We employed a murine asthma model, in which mice were treated by intranasal insufflation with allergens for 2-8weeks. We used both a pharmacologic approach using a highly specific FoxO1 inhibitor and genetic approaches using FoxO1 knockout mice (FoxO1fl/fl LysMcre). Cytokine level in biological fluids was measured by ELISA and the expression of encoding molecules by NanoString assay and qRT-PCR. We show that the levels of FoxO1 gene are significantly elevated in the airway macrophages of patients with mild asthma in response to subsegmental bronchial allergen challenge. Transcription factor FoxO1 regulates a pro-asthmatic phenotype of lung macrophages that is involved in the development and progression of chronic allergic airway disease. We have shown that inhibition of FoxO1 induced phenotypic conversion of lung macrophages and downregulates pro-asthmatic and pro-fibrotic gene expression by macrophages, which contribute to airway inflammation and airway remodeling in allergic asthma. Targeting FoxO1 with its downstream regulator IRF4 is a novel therapeutic target for controlling allergic inflammation and potentially reversing fibrotic airway remodeling.

P2X4R promotes airway remodeling by acting on the phenotype switching of bronchial smooth muscle cells in rats.

The P2X4 receptor (P2X4R) contributes to airway inflammation and airway remodeling in mice with allergic asthma. However, the molecular mechanism by which P2X4R affects the airway remodeling in allergic asthma remains largely unknown. We established an allergic asthma model by ovalbumin (OVA) inhalation in BALB/c mice. Compared with the mice in the control group, the expression of proliferating cell nuclear antigen (PCNA) increased and that of alpha-smooth muscle actin (α-SMA) decreased in the OVA-challenged mice. 5-BDBD, a P2X4R antagonist, alleviated the OVA-induced changes. To clarify the role of P2X4R in the phenotype switching of the bronchial smooth muscle, bronchial smooth muscle contractility and p38MAPK expression were investigated. Platelet-derived growth factor-BB (PDGF-BB) was used to activate the proliferation of primary-cultured rat bronchial smooth muscle cells (BSMCs). P2X4R, p38MAPK, and phenotype markers were evaluated using Western blotting or immunofluorescence. PDGF-BB administration increased the P2X4R and phospho-p38MAPK expression in BSMCs, and the increased phospho-p38MAPK expression was downregulated by silencing of the P2X4R mRNA. PDGF-BB stimulated the proliferation and synthetic phenotype of BSMCs, which was aggravated by a P2X4R agonist and alleviated by a P2X4R antagonist or silencing the P2X4R mRNA. The decreased contractile phenotype induced by PDGF-BB was alleviated by a P2X4R antagonist or by silencing the P2X4R mRNA. SB203580, p38MAPK inhibitor, inhibited the PDGF-BB-induced increasing of synthetic phenotype and the proliferation of BSMCs. These findings indicate that P2X4R acts directly on the phenotype switching of BSMCs. Inhibiting P2X4R can promote the contractile differentiation of BSMCs via p38MAPK signaling. Thus, the effect of P2X4R on airway remodeling indicates that this receptor could be a target for future drug candidates.

Effect of P2X4R on airway inflammation and airway remodeling in allergic airway challenge in mice

P2X4 receptor (P2X4R) is the most widely expressed subtype of the P2XRs in the purinergic receptor family. Adenosine triphosphate (ATP), a ligand for this receptor, has been implicated in the pathogenesis of asthma. ATP-P2X4R signaling is involved in pulmonary vascular remodeling, and in the proliferation and differentiation of airway and alveolar epithelial cell lines. However, the role of P2X4R in asthma remains to be elucidated. This aim of the present study was to investigate the effects of P2X4R in a murine experimental asthma model. The asthmatic model was established by the inhalation of ovalbumin (OVA) in BALB/c mice. The mice were treated with P2X4R-specific agonists and antagonists to investigate the role of this receptor in vivo. Pathological changes in the bronchi and lung tissues were examined using hematoxylin and eosin staining, Masson's trichrome staining and Alcian blue staining. The inflammatory cells in the bronchoalveolar lavage fluid were counted, and the expression levels of P2X4R, α-smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA) were detected using western blotting. In the OVA-challenged mice, inflammation, infiltration, collagen deposition, mucus production, and the expression levels of P2X4R and PCNA were all increased; however, the expression of α-SMA was decreased, compared with the mice in the control group. Whereas treatment with the P2X4R agonist, ATP, enhanced the allergic reaction, treatment with the P2X4R antagonist, 5-BDBD, attenuated the allergic reaction. The results suggested that ATP-P2X4R signaling may not only contribute to airway inflammation, but it may also contribute to airway remodeling in allergic asthma in mice.

Mitochondrial-targeted antioxidant therapy decreases transforming growth factor-β-mediated collagen production in a murine asthma model.

Asthma is a disease of acute and chronic inflammation in which cytokines play a critical role in orchestrating the allergic inflammatory response. IL-13 and transforming growth factor (TGF)-β promote fibrotic airway remodeling, a major contributor to disease severity. Improved understanding is needed, because current therapies are inadequate for suppressing development of airway fibrosis. IL-13 is known to stimulate respiratory epithelial cells to produce TGF-β, but the mechanism through which this occurs is unknown. Here, we tested the hypothesis that reactive oxygen species (ROS) are a critical signaling intermediary between IL-13 or allergen stimulation and TGF-β-dependent airway remodeling. We used cultured human bronchial epithelial cells and an in vivo mouse model of allergic asthma to map a pathway where allergens enhanced mitochondrial ROS, which is an essential upstream signal for TGF-β activation and enhanced collagen production and deposition in airway fibroblasts. We show that mitochondria in airway epithelium are an essential source of ROS that activate TGF-β expression and activity. TGF-β from airway epithelium stimulates collagen expression in fibroblasts, contributing to an early fibrotic response to allergen exposure in cultured human airway cells and in ovalbumin-challenged mice. Treatment with the mitochondrial-targeted antioxidant, (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (mitoTEMPO), significantly attenuated mitochondrial ROS, TGF-β, and collagen deposition in OVA-challenged mice and in cultured human epithelial cells. Our findings suggest that mitochondria are a critical source of ROS for promoting TGF-β activity that contributes to airway remodeling in allergic asthma. Mitochondrial-targeted antioxidants may be a novel approach for future asthma therapies.

Low-level laser therapy inhibits bronchoconstriction, Th2 inflammation and airway remodeling in allergic asthma

Low-level laser therapy (LLLT) controls bronchial hyperresponsiveness (BHR) associated with increased RhoA expression as well as pro-inflammatory mediators associated with NF-kB in acute lung inflammation. Herein, we explore if LLLT can reduce both BHR and Th2 cytokines in allergic asthma. Mice were studied for bronchial reactivity and lung inflammation after antigen challenge. BHR was measured through dose–response curves to acetylcholine. Some animals were pretreated with a RhoA inhibitor before the antigen. LLLT (660nm, 30mW and 5.4J) was applied on the skin over the right upper bronchus and two irradiation protocols were used. Reduction of BHR post LLLT coincided with lower RhoA expression in bronchial muscle as well as reduction in eosinophils and eotaxin. LLLT also diminished ICAM expression and Th2 cytokines as well as signal transducer and activator of transduction 6 (STAT6) levels in lungs from challenged mice. Our results demonstrated that LLLT reduced BHR via RhoA and lessened allergic lung inflammation via STAT6.

So-Cheong-Ryong-Tang, a herbal medicine, modulates inflammatory cell infiltration and prevents airway remodeling via regulation of interleukin-17 and GM-CSF in allergic asthma in mice.

Background:So-Cheong-Ryong-Tang (SCRT), herbal medicine, has been used for the control of respiratory disease in East Asian countries. However, its therapeutic mechanisms, especially an inhibitory effect on inflammatory cell infiltration and airway remodeling in allergic asthma are unclear.Objective:The present study investigated the mechanism of antiasthmatic effects of SCRT in allergic asthma in mice.Materials and Methods:We investigated the influence of SCRT on levels of interleukin-17 (IL-17), granulocyte/macrophage colony-stimulating factor (GM-CSF), IL-4, and interferon gamma (IFN-γ) in bronchoalveolar lavage fluid (BALF), ovalbumin (OVA)-specific IgE in serum, and histopathological changes in allergen-induced asthma.Results:So-Cheong-Ryong-Tang decreased levels of IL-17 and GM-CSF in BALF. IL-4, a Th2-driven cytokine, was also decreased by SCRT, but IFN-γ, a Th1-driven cytokine, was not changed. Levels of OVA-specific IgE in serum were also decreased by SCRT. With SCRT treatment, histopathological findings showed reduced tendency of inflammatory cell infiltration, and prevention from airway remodeling such as epithelial hyperplasia.Conclusion:In this study, we firstly demonstrated that regulation of IL-17 and GM-CSF production may be one of the mechanism contributed to a reduction of inflammatory cell infiltration and prevention from airway remodeling.

Can anti-IgE therapy prevent airway remodeling in allergic asthma?

Airway remodeling is a central feature of asthma. It is exemplified by thickening of the lamina reticularis and structural changes to the epithelium, submucosa, smooth muscle, and vasculature of the airway wall. Airway remodeling may result from persistent airway inflammation. Immunoglobulin E (IgE) is an important mediator of allergic reactions and has a central role in airway inflammation and asthma-related symptoms. Anti-IgE therapies (such as omalizumab) have the potential to block an early step in the allergic cascade and therefore have the potential to reduce airway remodeling. The reduction in free IgE levels following anti-IgE therapy leads to reductions in high-affinity IgE receptor (FcεRI) expression on mast cells, basophils, and dendritic cells. This combined effect results in attenuation of several markers of inflammation, including peripheral and bronchial tissue eosinophilia and levels of granulocyte macrophage colony-stimulating factor, interleukin (IL)-2, IL-4, IL-5, and IL-13. Considering the previously demonstrated anti-inflammatory effects of anti-IgE therapy, along with results from a small study showing continued benefit after discontinuation of long-term treatment, a larger study to assess its effect on markers of airway remodeling is underway.

The effects of antisense interleukin-4 gene transferred by recombinant adeno-associated virus vector on the airway remodeling in allergic rats

Background: Th2-derived cytokines, including interleukin-4 (IL-4), are considered to play an important role in the development of airway remodeling of asthma. Objectives: Our previous study has demonstrated that a recombinant adeno-associated virus containing antisense against IL-4 gene (rAAV-asIL4) vector could significantly suppress the expression of IL-4 protein and airway inflammation in the rat models of allergic asthma. In this study, we applied the rAAV-asIL4 vector to allergic rats to investigate the effects of anti-IL4 therapy on airway remodeling in allergic asthma. Methods: rAAV-asIL4 was used to infect the ovalbumin (OVA)-sensitized and challenged rats by tail-vein injection. IL-4 protein in bronchoalveolar lavage fluid (BALF) was detected by enzyme-linked immunosorbent assay. The number of eosinophils in BALF was counted. Transforming growth factor-beta1 (TGF-beta1) and TGF-beta2-positive cells in the peribronchial space were detected by immunohistochemical staining, and collagen deposition beneath the basement membrane was detected by Sirius red stain. The lung tissues were collected for histologic analysis of total bronchial wall area (WAt) and airway smooth muscle area (WAm). Results: rAAV-asIL4 significantly decreased IL-4 protein in BALF of OVA-sensitized and challenged rats. The number of eosinophils in BALF, the TGF-beta1 and TGF-beta2-positive cells in the peribronchial space were also suppressed. Moreover, the rAAV-asIL4 treatment inhibited the area of Sirius red staining in airways and the increase in WAt and WAm. Conclusion: These results suggest that rAAV-asIL4 may attenuate the airway remodeling process relevant to the inhibition of airway inflammation. This study provides elementary evidence for the potential utility of rAAV-asIL4 as an approach to gene therapy for asthmatic airway remodeling.

IL-13-induced proliferation of airway epithelial cells: mediation by intracellular growth factor mobilization and ADAM17

BackgroundThe pleiotrophic cytokine interleukin (IL)-13 features prominently in allergic and inflammatory diseases. In allergic asthma, IL-13 is well established as an inducer of airway inflammation and tissue remodeling. We demonstrated previously that IL-13 induces release of transforming growth factor-α (TGFα) from human bronchial epithelial cells, with proliferation of these cells mediated by the autocrine/paracrine action of this growth factor. TGFα exists as an integral membrane protein and requires proteolytic processing to its mature form, with a disintegrin and metalloproteinase (ADAM)17 responsible for this processing in a variety of tissues.MethodsIn this study, normal human bronchial epithelial (NHBE) cells grown in air/liquid interface (ALI) culture were used to examine the mechanisms whereby IL-13 induces release of TGFα and cellular proliferation. Inhibitors and antisense RNA were used to examine the role of ADAM17 in these processes, while IL-13-induced changes in the intracellular expression of TGFα and ADAM17 were visualized by confocal microscopy.ResultsIL-13 was found to induce proliferation of NHBE cells, and release of TGFα, in an ADAM17-dependent manner; however, this IL-13-induced proliferation did not appear to result solely from ADAM17 activation. Rather, IL-13 induced a change in the location of TGFα expression from intracellular to apical regions of the NHBE cells. The apical region was also found to be a site of significant ADAM17 expression, even prior to IL-13 stimulation.ConclusionResults from this study indicate that ADAM17 mediates IL-13-induced proliferation and TGFα shedding in NHBE cells. Furthermore, they provide the first example wherein a cytokine (IL-13) induces a change in the intracellular expression pattern of a growth factor, apparently inducing redistribution of intracellular stores of TGFα to the apical region of NHBE cells where expression of ADAM17 is prominent. Thus, IL-13-induced, ADAM17-mediated release of TGFα, and subsequent epithelial cell proliferation, could contribute to the epithelial hypertrophy, as well as other features, associated with airway remodeling in allergic asthma.

Role of prostaglandin I2 in airway remodeling induced by repeated allergen challenge in mice.

Recently, we demonstrated that prostaglandin (PG)I2 has a regulatory role in allergic responses through the receptor, IP; however, the role of PGI2 in airway remodeling associated with chronic airway inflammation has not been elucidated. In the present study, we examined the role of PGI2 in allergen-induced airway remodeling using IP gene-deficient mice. Mice were sensitized to ovalbumin (OVA) with alum, and exposed daily for 3 wk to aerosolized OVA. Twenty-four hours after the final antigen inhalation, bronchoalveolar lavage, biochemical, and histopathologic examinations were performed. In wild-type mice, prolonged allergen exposure in sensitized animals induced the increases in the numbers of inflammatory leukocytes (including eosinophils and lymphocytes), levels of T helper type 2 (Th2) cytokines (interleukin [IL]-4, IL-5, and IL-13), levels of OVA-specific immunoglobulin (Ig)E and IgG1 in serum, and amount of hydroxyproline in the right lungs associated with transforming growth factor-beta1 levels in bronchoalveolar lavage fluid. Moreover, goblet cell hyperplasia and subepithelial fibrosis were also appreciated after repeated allergen challenge. In contrast, the disruption of IP gene significantly augmented all these parameters. These findings suggest that PGI2 has a regulatory role in allergen-induced airway remodeling as well as airway eosinophilic inflammation, Th2 cytokine production and IgE production, and that a PGI2 agonist is a therapeutic approach for the treatment of airway remodeling in allergic asthma.