Tongxinluo Boosts the Effect of Atorvastatin in Treatment of Atherosclerosis With COPD by Maintaining the Pulmonary Microvascular Barrier

Abstract Background: Atherosclerosis (AS) is a common comorbidity of chronic obstructive pulmonary disease (COPD) and the main cause of death in patients with COPD. Systemic inflammation is a significant mechanism of COPD with AS. The dysfunction of pulmonary microvascular barrier is involved in the formation of chronic inflammation in COPD, and its functional disruption will induce systemic inflammation. Atorvastatin (Ato) is a common medicine for the treatment of AS; however, the effect is not ideal for COPD combined with AS. Tongxinluo (TXL) improves the function of vascular endothelial cells. This study aims to prove that the impairment of pulmonary microvascular barrier function participated in the process of COPD aggravating AS and investigated whether TXL enhances the therapeutic effect of Ato on COPD with AS by protecting the pulmonary microvascular endothelial barrier function. Methods: In vivo, the COPD with AS model of ApoE-/- mice was established by cigarette smoke combined with a high-fat diet. The animals were administered TXL (1.5 g/kg/day), Ato (10 mg/kg/day), and TXL+Ato once a day for 20 weeks. Then, lung function, lung microvascular permeability, lung inflammation, systemic inflammation, serum lipid level, atheromatous plaque formation, and the biomarker of endothelial damage were measured. In vitro, human pulmonary microvascular endothelial cells (HPMECs) were pretreated with TXL for 6 h and incubated with cigarette smoke extract (CSE) for 24 h to establish a model of CSE-induced pulmonary microvascular barrier dysfunction. The permeability of the endothelial monolayer, inflammatory cytokines, endothelial damage biomarkers, tight junction proteins were determined. Results: Cigarette smoking significantly exacerbated, which induced by high fat diet, the pulmonary function decline, pulmonary microvascular endothelial barrier dysfunction, pulmonary and systemic inflammation, and atherosclerotic plaque. These changes were reversed by TXL-Ato combination; the combination therapeutic effect was better than that of Ato alone. In addition, TXL protected the function of HPMEC barrier and inhibited the inflammation in CSE-induced HPMECs.Conclusions: COPD aggravates AS, the mechanism may be the destruction of pulmonary microvascular barrier function and thus lung inflammation triggers systemic inflammation. In treating COPD with AS, TXL enhances the anti-AS effect of Ato protecting the pulmonary microvascular barrier.