Carbenoxolone decreases monocrotaline‑induced pulmonary inflammation and pulmonary arteriolar remodeling in rats by decreasing the expression of connexins in T lymphocytes

Abstract

The adaptive immune response mediated by T lymphocytes is a well-established factor in the pathogenesis of pulmonary inflammation. changes in the expression of various connexins (cxs) or disruption of connexin-mediated cellular communication in T lymphocytes contribute to inflammation or tissue remodeling. The aim of the present study was to investigate the potential therapeutic value of blocking cxs in a monocrotaline (McT)-induced pulmonary inflammation rat model. Carbenoxolone (CBX) was used to inhibit connexin-mediated cellular communication. An McT rat model was established by intraperitoneal (i.p.) injection of a single dose of MCT (60 mg/kg), and CBX treatment (20 µg/kg/day, i.p.) was initiated on the day following McT treatment for 28 days. Vehicle-treated male Sprague-dawley rats were used as the negative control. The McT rat model was evaluated by measuring the pulmonary artery flow acceleration time and right ventricular hypertrophy index (RVHI). Histopathological features of the lung tissues and pulmonary arteriolar remodeling were assessed. The proportions of T lymphocyte subtypes, cx40/cx43 expression in the T cell subtypes and the cytokine levels in the plasma and the lung tissues were also analyzed. Pharmacological inhibition of Cxs using CBX attenuated MCT-induced right ventricular hypertrophy, pulmonary arteriolar remodeling, lung fibrosis and inflammatory cell infiltration by decreasing the RVHI, pulmonary arterial wall thickening, collagen deposition and pro-inflammatory cytokines production as well as CD3 + and cd4 + T cell accumulation in lung tissues of McT-treated rats. Furthermore, flow cytometry analysis revealed that CBX may inhibit McT-induced cx40 and cx43 expression in cd4 + and cd8 + T lymphocytes in lung tissues. The present study provides evidence that pharmacological inhibition of cxs may attenuate McT-induced pulmonary arteriolar remodeling and pulmonary inflammatory response, at least in part, by decreasing cx expression. The results highlight the critical role of cxs in T lymphocytes in the McT-induced pulmonary inflammatory response and that targeting of Cxs may be a potential therapeutic method for treating pulmonary inflammatory diseases.

Importance of Cx43 for Right Ventricular Function

“…The aforementioned studies all demonstrate that protection against PH is associated with preservation of connexin expression and/or localization. In contrast, monocrotalinetreated rats have an increased number of Cx40-and Cx43-expressing CD4 + and CD8 + T cells in lung tissue and the administration of the unspecific gap junction blocker carbenoxolone decreases the expression of these connexins and reduces RV hypertrophy in monocrotaline-treated rats [100]. These data show that the inhibition of connexins decrease the monocrotaline-induced pulmonary inflammatory response.…”

A Systematic Study of the Mechanism of Acacetin Against Sepsis Based on Network Pharmacology and Experimental Validation

“…p-p65 is the key target of the classic inflammation-related NF-κB signalling pathway, CD86 is a surface marker of M1polarized macrophages, and iNOS is a pro-inflammatory molecule associated with the inflammatory process. Our previous research on Cx43 showed that carbenoxolone decreased monocrotaline-induced pulmonary inflammation in rats by decreasing the expression of Cxs in T lymphocytes (Zhang et al, 2020). Angiotensin II induced RAW264.7 macrophage polarization toward the M1 phenotype through the Cx43/NF-κB pathway (Wu et al, 2020).…”

Inhibition of KIR2.1 decreases pulmonary artery smooth muscle cell proliferation and migration

“…Two professional pathologists randomly selected 20 different non-overlapping fields from each section and analyzed PVR and lung fibrosis with Image-Pro Plus v.6.0 software (Media Cybernetics, Inc.). The pulmonary fibrosis index was analyzed by calculating the ratio of the total area of collagen to the total area of connective tissue in each field of view, as previously described (32).…”