N‐Acetylcysteine potentiates the haemodynamic‐improving effect of sildenafil in a rabbit model of acute pulmonary thromboembolism via the p38 MAPK pathway

Abstract

Summary The current study aimed to investigate the effects of sildenafil and N‐acetylcysteine (NAC) on the haemodynamics in a rabbit model of acute pulmonary thromboembolism (APT). We developed an APT model using healthy male China big‐ear rabbits (2.7 ± 0.4 kg). The rabbits were divided into five groups subjected to various interventions. We recorded the haemodynamic parameters and assessed the oxidative stress and lipid peroxidation response in the groups. Additionally, we detected apoptosis‐associated molecules, FoxO1, Bad and Bcl‐2, in the lung tissue. Gelatine zymography was used to detect matrix metalloproteinase (MMP) activity in bronchoalveolar lavage (BLA). Pulmonary artery endothelial cells were isolated, and their apoptosis rates and MMP activity were assayed. N‐acetylcysteine potentiated the haemodynamic‐improving effect of sildenafil and significantly inhibited the oxidative stress response. N‐acetylcysteine combined with sildenafil decreased MMP‐2 and MMP‐9 activity and NO consumption and inhibited apoptosis of pulmonary arterial endothelial cells. Moreover, NAC combined with sildenafil inhibited the expression of MCP‐1 and p‐p38 MAPK. Thus, NAC potentiates the haemodynamic‐improving effect of sildenafil in a rabbit model of acute pulmonary thromboembolism via the MCP‐1 and p38 MAPK signalling pathway. This study may provide a promising treatment method for APT.

N‑acetyl cysteine inhibits lipopolysaccharide‑induced apoptosis of human umbilical vein endothelial cells via the p38MAPK signaling pathway

“…NAC has been used as an antioxidant in neurodegenerative diseases, chronic lung diseases, cardiovascular diseases and other oxidative diseases (23)(24)(25). apart from the antioxidant properties, nac has been shown to induce hemodynamic improvements in a rabbit model of acute pulmonary thromboembolism; the effect was mediated via the p38MaPK pathway (26). The role of NAC in preventing endothelial apoptosis and its beneficial effect on cell survival by acting through the p38MaPK signaling pathway has evoked considerable interest in recent years.…”

Sildenafil Improves Hemodynamic Changes Caused by Acute Pulmonary Embolism by Inhibiting Rho-kinase Activity

“…Current functional studies of sildena l have focused on the relief of disease, hemodynamics, and exercise tolerance in PH patients. Previous experiments showed that pretreatment with sildena l effectively prevented PAH induced by APE, whereas acetylcysteine infusion enhanced this bene cial effect by inhibiting oxidative stress and lipid peroxidation 22 . However, the mechanism by which sildena l acts to improve hemodynamics in PAH caused by APE remains unclear.…”

The antioxidant N-acetylcysteine promotes immune response and inhibits epithelial-mesenchymal transition to alleviate pulmonary fibrosis in chronic obstructive pulmonary disease by suppressing the VWF/p38 MAPK axis

“…Furthermore, the obtained data suggested that NAC inhibited p38 MAPK phosphorylation by reducing the VWF expression to inhibit the pulmonary fibrosis in COPD. Apart from the antioxidant properties, NAC is known to suppress the activation of p38 MAPK pathway (Zhang et al 2019 ). The activation of p38 MAPK is also found in COPD (Khorasani et al 2015 ).…”