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Ma W.-L.,Huazhong University of Science and Technology | Ma W.-L.,Key Laboratory of Pulmonary Diseases | Cai P.-C.,Huazhong University of Science and Technology | Xiong X.-Z.,Huazhong University of Science and Technology | And 3 more authors.
Journal of Huazhong University of Science and Technology - Medical Science | Year: 2013

FIZZ/RELM is a new gene family named "found in inflammatory zone" (FIZZ) or "resistin-like molecule" (RELM). FIZZ1/RELMα is specifically expressed in lung tissue and associated with pulmonary inflammation. Chronic cigarette smoking up-regulates FIZZ1/RELMα expression in rat lung tissues, the mechanism of which is related to cigarette smoking-induced airway hyperresponsiveness. To investigate the effect of exercise training on chronic cigarette smoking-induced airway hyperresponsiveness and up-regulation of FIZZ1/RELMα, rat chronic cigarette smoking model was established. The rats were treated with regular exercise training and their airway responsiveness was measured. Hematoxylin and eosin (HE) staining, immunohistochemistry and in situ hybridization of lung tissues were performed to detect the expression of FIZZ1/RELMα. Results revealed that proper exercise training decreased airway hyperresponsiveness and pulmonary inflammation in rat chronic cigarette smoking model. Cigarette smoking increased the mRNA and protein levels of FIZZ1/RELMα, which were reversed by the proper exercise. It is concluded that proper exercise training prevents up-regulation of FIZZ1/RELMα induced by cigarette smoking, which may be involved in the mechanism of proper exercise training modulating airway hyperresponsiveness. © 2013 Huazhong University of Science and Technology and Springer-Verlag Berlin Heidelberg.


Ye H.,Huazhong University of Science and Technology | Ye H.,Key Laboratory of Pulmonary Diseases | Cai P.-C.,Huazhong University of Science and Technology | Zhou Q.,Key Laboratory of Pulmonary Diseases | And 3 more authors.
Wound Repair and Regeneration | Year: 2011

Exposed to inflammatory factors or cytokines, fibroblasts appear to play additional roles beyond the deposition of extracellular matrix. It has been reported that tumor necrosis factor-α (TNF-α) induces the production of matrix metalloproteinase-2 (MMP-2) and transforming growth factor-β1 (TGF-β1) in fibroblasts. In this study, we demonstrated that the active MMP-2 secreted by lung fibroblasts reached the peak level at 12 hours after TNF-α treatment, whereas, by adding anti-TGF-β1 antibody in the culture medium, the MMP-2 production in response to TNF-α was maintained at high levels after 24 hours of treatment. We also confirmed that TNF-α induced up-regulation of active TGF-β1 and exogenous TGF-β1 induced down-regulation of MMP-2 synthesis in lung fibroblasts. Moreover, an increased MMP-2 level was observed in a rat model with pulmonary inflammation and fibrosis induced by bleomycin-A5. This revealed that MMP-2 in the lung reached the peak level when TNF-α reached the peak level at the 7th day, and then MMP-2 decreased along with an increase in the TGF-β1 level. Taken together, our results demonstrate that TNF-α induced an increase of MMP-2 and TGF-β1 in lung fibroblasts, and the TGF-β1 attenuated the up-regulation of MMP-2. This suggests that MMP-2 secreted from fibroblasts modulated by TNF-α/TGF-β1 might play an important role in pulmonary inflammation and fibrosis. © 2011 by the Wound Healing Society.


Li F.-Z.,Huazhong University of Science and Technology | Cai P.-C.,Huazhong University of Science and Technology | Song L.-J.,Huazhong University of Science and Technology | Zhou L.-L.,Huazhong University of Science and Technology | And 15 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2015

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease of unknown cause that typically leads to respiratory failure and death within 3-5years of diagnosis. TGF-β1 is considered a major profibrotic factor. However, TGF-β1 is necessary but not sufficient to the pathogenesis of fibrotic lesion of the lungs. Recent observations have revealed that calpain, a calcium dependent protease, plays a pivotal role in tissue remodeling and fibrosis. However, the mechanism of calpain mediating pulmonary fibrosis is not understood. Calpain conditional knockout (ER-Cre+/-capns1flox/flox) mice and primary human lung fibroblasts (HLFs) were used here to investigate the relationship between calpain and TGF-β1. Calpain knockout mice were protected from fibrotic effects of bleomycin. Bleomycin induced increases in TGF-β1 via calpain activation in HLFs. Moreover, TGF-β1 also activated calpain. This crosstalk between calpain activation and TGF-β1 triggered the downstream signaling pathway including TGF-β1 Smad2/3 and non-Smad (Akt) pathways, as well as collagen-I synthesis. Taken together, our data indicate that the crosstalk between calpain activation and TGF-β1 augments collagen-I synthesis in HLFs and in pulmonary fibrosis. Intervention in the crosstalk between calpain activation and TGF-β1 is a novel potential strategy to prevent pulmonary fibrosis. © 2015.


Du Y.,Huazhong University of Science and Technology | Du Y.,Key Laboratory of Pulmonary Diseases | Zhao J.,Huazhong University of Science and Technology | Zhao J.,Key Laboratory of Pulmonary Diseases | And 22 more authors.
American Journal of Respiratory Cell and Molecular Biology | Year: 2014

Airway hyperresponsiveness (AHR) in asthma is predominantly caused by increased sensitivity of bronchial smooth muscle cells (BSMCs) to stimuli. The sarcoplasmic reticulum (SR)-Ca21 release channel, known as ryanodine receptor (RyR), mediates the contractive response of BSMCs to stimuli. FK506-binding protein 12.6 kD (FKBP12.6) stabilizes the RyR2 channel in a closed state. However, the interaction of FKBP12.6 with RyR2 in AHR remains unknown. This study examined the interaction of FKBP12.6 with RyR2 in BSMCs inAHRof asthma. The interaction of FKBP12.6 with RyR2 and FKBP12.6 expression was determined in a rat asthma model and in BSMCs treated with inflammatory cytokines. The calcium responses to contractile agonists were determined in BSMCs with overexpression and knockdown of FKBP12.6. Asthmatic serum, IL-5, IL-13, and TNF-a enhance the calcium response of BSMCs to contractile agonists and cause dissociation of FKBP12.6 from RyR2 and a decrease in FKBP12.6 gene expression in BSMCs in culture and in ovalbumin (OVA)-sensitized and -challenged rats. Knockdown of FKBP12.6 inBSMCscauses a decrease in the association of RyR2 with FKBP12.6 and an increase in the calcium response of BSMCs. Overexpression of FKBP12.6 increases the association of FKBP12.6 with RyR2, decreases the calcium response of BSMCs, and normalizes airway responsiveness in OVA-sensitized and -challenged rats. Dissociation of FKBP12.6 from RyR2 in BSMCs is responsible for the increased calcium response contributing to AHR in asthma. Manipulating the interaction of FKBP12.6 with RyR2 might be a novel and useful treatment for asthma. Copyright © 2014 by the American Thoracic Society.


Chen L.-J.,Huazhong University of Science and Technology | Ye H.,Huazhong University of Science and Technology | Ye H.,Key Laboratory of Pulmonary Diseases | Zhang Q.,Huazhong University of Science and Technology | And 15 more authors.
Toxicology and Applied Pharmacology | Year: 2015

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease characterized by the development of subpleural foci of myofibroblasts that contribute to the exuberant fibrosis. Recent studies revealed that pleural mesothelial cells (PMCs) undergo epithelial-mesenchymal transition (EMT) and play a pivotal role in IPF. In animal model, bleomycin induces pulmonary fibrosis exhibiting subpleural fibrosis similar to what is seen in human IPF. It is not known yet whether bleomycin induces EMT in PMCs. In the present study, PMCs were cultured and treated with bleomycin. The protein levels of collagen-I, mesenchymal phenotypic markers (vimentin and α-smooth muscle actin), and epithelial phenotypic markers (cytokeratin-8 and E-cadherin) were measured by Western blot. PMC migration was evaluated using wound-healing assay of culture PMCs in vitro, and in vivo by monitoring the localization of PMC marker, calretinin, in the lung sections of bleomycin-induced lung fibrosis. The results showed that bleomycin induced increases in collagen-I synthesis in PMC. Bleomycin induced significant increases in mesenchymal phenotypic markers and decreases in epithelial phenotypic markers in PMC, and promoted PMC migration in vitro and in vivo. Moreover, TGF-β1-Smad2/3 signaling pathway involved in the EMT of PMC was demonstrated. Taken together, our results indicate that bleomycin induces characteristic changes of EMT in PMC and the latter contributes to subpleural fibrosis. © 2015.

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