Abstract
RationalePulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance leading to right ventricular failure and death. Recent studies have suggested that chronic inflammatory processes are involved in the pathogenesis of PAH. However, the molecular and cellular mechanisms driving inflammation have not been fully elucidated.ObjectivesTo elucidate the roles of high mobility group box 1 protein (HMGB1), a ubiquitous DNA-binding protein with extracellular pro-inflammatory activity, in a rat model of PAH.MethodsMale Sprague-Dawley rats were administered monocrotaline (MCT). Concentrations of HMGB1 in bronchoalveolar lavage fluid (BALF) and serum, and localization of HMGB1 in the lung were examined over time. The protective effects of anti-HMGB1 neutralizing antibody against MCT-induced PAH were tested.ResultsHMGB1 levels in BALF were elevated 1 week after MCT injection, and this elevation preceded increases of other pro-inflammatory cytokines, such as TNF-α, and the development of PAH. In contrast, serum HMGB1 levels were elevated 4 weeks after MCT injection, at which time the rats began to die. Immunohistochemical analyses indicated that HMGB1 was translocated to the extranuclear space in periarterial infiltrating cells, alveolar macrophages, and bronchial epithelial cells of MCT-injected rats. Anti-HMGB1 neutralizing antibody protected rats against MCT-induced lung inflammation, thickening of the pulmonary artery wall, and elevation of right ventricular systolic pressure, and significantly improved the survival of the MCT-induced PAH rats.ConclusionsOur results identify extracellular HMGB1 as a promoting factor for MCT-induced PAH. The blockade of HMGB1 activity improved survival of MCT-induced PAH rats, and thus might be a promising therapy for the treatment of PAH.
Highlights
Pulmonary arterial hypertension (PAH), characterized by increased pulmonary vascular resistance leading to right ventricular failure, is a progressive disease with a poor prognosis [1]
Immunohistochemical analyses indicated that high mobility group box 1 protein (HMGB1) was translocated to the extranuclear space in periarterial infiltrating cells, alveolar macrophages, and bronchial epithelial cells of MCT-injected rats
Nuclear protein HMGB1 is released to the extracellular space during the early stage of MCT-induced PAH we performed time-course analysis of pro-inflammatory cytokine levels, including HMGB1, monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-a (TNF-a), and IL-1b, in bronchoalveolar lavage fluid (BALF) and serum of MCT-induced PAH rats
Summary
Pulmonary arterial hypertension (PAH), characterized by increased pulmonary vascular resistance leading to right ventricular failure, is a progressive disease with a poor prognosis [1]. The main pathological finding related to PAH is an abnormal proliferation of endothelial cells and smooth muscle cells resulting in obstruction of small pulmonary arteries [2,3]. Recent studies have suggested that inflammatory processes are involved in the initiation and progression of PAH and the remodeling of the pulmonary vasculature [4,5]. Proinflammatory cytokines and chemokines, such as tumor necrosis factor-a (TNF-a), interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), and regulated upon activation, normal T-cell expressed, and secreted (RANTES), contribute to the recruitment of leukocytes, the induction of endothelin-1, and the proliferation of smooth muscle cells [7,8,9,10]. It is widely known that inflammation plays a prominent role in the development of PAH, molecular and cellular mechanisms driving inflammation remain poorly defined
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