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Airway epithelial cells, the first barrier of the respiratory tract, play an indispensable role in innate immunity. Integrin β4 (ITGB4) is a structural adhesion molecule that is involved in the pathological progression of acute inflammatory diseases and is downregulated in asthmatic patients. Research has shown that endothelial ITGB4 has proinflammatory properties in acute lung injury (ALI). However, the role of epithelial ITGB4 in a murine ALI model is still unknown. This study investigated the role of ITGB4 in lipopolysaccharide (LPS)-induced ALI. We found that ITGB4 in the airway epithelium had remarkably increased after the introduction of LPS in vivo and in vitro. Then, we constructed airway epithelial cell-specific ITGB4 knockout (ITGB4 -/- ) mice to study its role in ALI. At a time point of 12 h after the tracheal injection of LPS, ITGB4 -/- mice showed increased macrophages (mainly M1-type macrophages) and neutrophil infiltration into the lungs; inflammation-related proteins including interleukin (IL)-6, tumor necrosis factor, and IL-17A were significantly elevated compared to their levels in ITGB4 +/+ mice. Furthermore, we investigated the role of ITGB4 in the anti-inflammatory response. Intriguingly, in the ITGB4 -/-  + LPS group, we found significantly reduced expression of anti-inflammatory factors, including IL-10 messenger RNA (mRNA) and ARG-1 mRNA. We also observed that monocyte chemotactic protein (MCP-1) increased significantly both in vivo and in vitro. Airway epithelium activates macrophages, most likely driven by MCP-1, which we confirmed in the coculture of epithelia and macrophages. These phenomena indicate that ITGB4 in airway epithelial cells plays an important role in the process of inflammation and activation of macrophages in ALI. Overall, these data demonstrated a novel link between airway epithelial ITGB4 and the inflammatory response in LPS-induced ALI., (© 2021 Wiley Periodicals LLC.)

Our previous studies provided evidence that bombesin receptor-activated protein (BRAP), encoded by C6ORF89, is widely expressed in human airway epithelial cells and may play a role in the stress response of lung epithelia. In this study, we demonstrated that BRAP has a regulatory effect on NF-κB transcriptional activity in cultured human bronchial epithelial cells (HBECs). BRAP overexpression by gene transfer inhibited both basal and inducible NF-κB transcriptional activity in HBECs, whereas BRAP knockdown had the opposite effect. BRAP was shown to regulate NF-κB activity by enhancing histone deacetylase (HDAC) activity. In addition, BRAP might increase HDAC activity that leads to NF-κB activation via its putative C-terminal domain. Our study suggests that the BRAP protein is an important regulator of immune and inflammatory responses in the human airway epithelium., (© 2015 Wiley Periodicals, Inc.)

Bombesin receptor activated protein (BRAP) was identified in a bacterial two-hybrid screen for proteins interacting with bombesin receptor subtype-3 (BRS-3). We found that BRAP is widely expressed in the airway epithelium of human lungs and may play a role during the stress response of lung epithelium. In this work, we explored the potential roles of BRAP in the antigen presenting function of human bronchial epithelial cells (HBECs). Overexpression of a BRAP recombinant protein in a human bronchial epithelial cell line resulted in a reduction of FITC-OVA uptake by HBECs, which indicated that the antigen uptake ability is inhibited. The analysis of the protein expression of surface molecules including B7 homologs and the major histocompactability complex (MHC) class II molecules showed that the expression levels of HLA-DR and B7DC increased while the levels of B7-H1 and B7.2 decreased. Since those surface molecules are all related to antigen presenting process, the altered expression pattern of those molecules provides further evidence showing that BRAP overexpression leads to a change in antigen presenting function of HBECs. Moreover, overexpression of BRAP in HBECs caused a decrease of co-cultured lymphocytes proliferation and a changed pattern of cytokines produced by lymphocytes in the presence of FITC-OVA, which indicated that changes in the maturation pattern and functions of co-cultured lymphocytes were induced by BRAP overexpression. Overall, our results suggested that overexpression of BRAP may play a role during the antigen presenting process of bronchial epithelium by inhibiting the antigen uptake ability of bronchial epithelial cells., (Copyright © 2012 Wiley Periodicals, Inc.)

Cystic fibrosis transmembrane conductance regulator (CFTR) is an apical membrane chloride channel critical to the regulation of fluid, chloride, and bicarbonate transport in epithelia and other cell types. The most common cause of cystic fibrosis (CF) is the abnormal trafficking of CFTR mutants. Therefore, understanding the cellular machineries that transit CFTR from the endoplasmic reticulum to the cell surface is important. Vasoactive intestinal polypeptide (VIP) plays an important role in CFTR-dependent chloride transport. The present study was designed to observe the affection of VIP on the trafficking of CFTR, and channel gating in human bronchial epithelium cells (HBEC). Confocal microscopy revealed CFTR immunofluorescence extending from the apical membrane deeply into the cell cytoplasm. After VIP treatment, apical extension of CFTR immunofluorescence into the cell was reduced and the peak intensity of CFTR fluorescence shifted towards the apical membrane. Western blot showed VIP increased cell surface and total CFTR. Compared with the augmented level of total CFTR, the surface CFTR increased more markedly. Immunoprecipitation founded that the mature form of CFTR had a marked increase in HBEC treated with VIP. VIP led to a threefold increase in Cl(-) efflux in HBEC. Glibenclamide-sensitive and DIDS-insensitive CFTR Cl(-) currents were consistently observed after stimulation with VIP (10(-8) mol/L). The augmentation of CFTR Cl(-) currents enhanced by VIP (10(-8) mol/L) was reversed, at least in part, by the protein kinase A (PKA) inhibitor, H-89 and the protein kinase C (PKC) inhibitor, H-7, suggesting PKA and PKC participate in the VIP-promoted CFTR Cl(-) currents., (Copyright © 2010 Wiley-Liss, Inc.)

Adhesion molecules play vital roles in airway hyperresponsiveness (AHR) or airway inflammation. Our previous study indicated that adhesion molecule catenin alpha-like 1 (CTNNAL1) is relevant closely to asthma susceptibility, but its biological function or significance is still unclear. In the present study, we observed the temporal and spatial distribution of CTNNAL1 expression in mouse lung tissue with the OVA-sensitized asthma model and found that the level of CTNNAL1 mRNA showed a prominent negative correlation with pulmonary resistance (R(L)). To study the function of CTNNAL1 in airway, effects of CTNNAL1 on proliferation and wound repair activity of human bronchial epithelial cells (HBEC) was investigated with antisense oligonucleotide (ASO) technique. The results showed that: (1) CTNNAL1 ASO could decelerate the repairing velocity and proliferation of HBEC; (2) CTNNAL1 expression was increased on the edge cells of mechanic wounded area in culture; (3) extracellular matrix component fibronectin (Fn) obviously promoted wound repair activity and proliferation of HBEC, which could be blocked by CTNNAL1 ASO; (4) Western blot showed that Fn could promote FAK phosphorylation, which also be inhibited by CTNNAL1 ASO. In conclusion, the level of CTNNAL1 mRNA expression is highly correlated to airway resistance; CTNNAL1 may contribute to the wound repair and proliferation of HBEC. Furthermore, it may serve to Fn mediated cell-extracellular adhesion and its signal transduction., (Copyright 2007 Wiley-Liss, Inc.)