Inactivated Pseudomonas aeruginosa inhibits hypoxia-induced pulmonary hypertension by preventing TGF-β1/Smad signaling

Abstract

Pseudomonas aeruginosa is one of the common colonizing bacteria of the human body and is an opportunistic pathogen frequently associated with respiratory infections. Inactivated P. aeruginosa (IPA) have a variety of biological effects against inflammation and allergy. Transforming growth factor-β (TGF-β) signaling plays a critical role in the regulation of cell growth, differentiation, and development in a wide range of biological systems. The present study was designed to investigate the effects of IPA on TGF-β/Smad signaling in vivo, using a hypoxia-induced pulmonary hypertension (PH) rat model. Sprague Dawley rats (n=40) were exposed to 10% oxygen for 21 days to induce PH. At the same time, IPA was administered intravenously from day 1 to day 14. Mean pulmonary artery pressure (mPAP) and the right ventricle (RV) to left ventricle plus the interventricular septum (LV+S) mass ratio were used to evaluate the development of PH. Vessel thickness and density were measured using immunohistochemistry. Primary arterial smooth muscle cells (PASMCs) were isolated and the proliferation of PASMCs was assayed by flow cytometry. The production of TGF-β1 in cultured supernatant of PASMCs was assayed by ELISA. The expression levels of α-smooth muscle actin (α-SMA), TGF-β1 and phospho-Smad 2/3 in PASMCs were assayed by western blot. Our data indicated that IPA attenuated PH, RV hypertrophy and pulmonary vascular remodeling in rats, which was probably mediated by restraining the hypoxia-induced overactive TGF-β1/Smad signaling. In conclusion, IPA is a promising protective treatment in PH due to the inhibiting effects on TGF-β1/Smad 2/3 signaling.

Mechanism of the effect of tanshinone IIA epithelial-mesenchymal transition via the TGF-β1/smad pathway in human alveolar epithelial cell line A549

“…Of these extracellular cues, TGF-β1 has a predominant role [25]. TGF-β1 is a multifunctional cytokine, a potent inhibitor of epithelial cell repair, and an inducer of PF through regulating cell proliferation, growth, differentiation, and movement [26]. Smad family protein is the intracellular transduction molecule of TGF-β family reported to be involved in the modulation of cell proliferation and migration [27].…”

“…As a component of cytoskeleton, α-SMA is expressed by myofibroblasts, which are a heterogeneous population of highly profibrogenic cells; high levels indicate the progression of fibrosis with collagen deposition. In experimental studies on fibrosis, this interstitial marker is highly expressed a few days after induction of fibrosis [23,24].…”

MicroRNA-542-3p inhibits oral squamous cell carcinoma progression by inhibiting ILK/TGF-β1/Smad2/3 signaling

“…The overexpression of miR-542-3p significantly inhibited the activation of β-catenin and nuclear factor-κB signaling pathways that promote carcinogenesis [ 25 ]. TGF-β signaling pathway also plays a very critical role in regulating cell growth, differentiation, and development of biological systems [ 29 , 30 ]. TGF-β1 promotes tumor cell growth through the Smad-ILK signaling pathway by increasing Smad2/3 and ILK expression [ 31 ].…”

Prediction of target genes for miR‐140‐5p in pulmonary arterial hypertension using bioinformatics methods

“…JAG1 and ADAM10 are indispensable components of Notch signaling pathway, which were predicted as downstream targets of miR‐140‐5p in our analysis, suggesting that lack of miR‐140‐5p might promote the development of PAH by upregulation of JAG1 and ADAM10 genes and therefore activation of Notch3 cascade. In addition, activation of TGF‐beta1/Smad4 signaling promotes a proliferative PASMC phenotype and induces PAH in rat . We found that TGF‐betaR1 and smad4 were possible downstream targets of miR‐140‐5p, reduction in miR‐140‐5p in PAH might stimulate TGF‐beta1/Smad4 pathway by upregulating TGF‐betaR1 and smad4.…”