Pulmonary hypertension after pneumonectomy: a preclinical model in rats and human pulmonary endothelial cells.

OBJECTIVES: Pulmonary hypertension and heart disease contribute to the high morbidity rate following pneumonectomy (PN). The pathophysiology is still poorly understood. The objective was to investigate the consequences of PN on cardiopulmonary function in rats and to explore in vitro the involved mechanisms. METHODS: Sixty Sprague-Dawley male rats randomly underwent either a right PN (PN group) or sham surgery. Ten rats per group were sacrificed on postoperative days 3, 7 and 28. Cardiopulmonary alterations were investigated by echocardiographic, haemodynamic and histological analyses. In vitro, the shear stress was reproduced using a Flexcell Tension™ cyclic stretch on cultured human pulmonary endothelial cells (P-ECs) to investigate the impact on pulmonary artery smooth muscle cell (PA-SMC) growth. Data are expressed as mean ± SD. RESULTS: Mean pulmonary arterial pressure gradually increased in the PN group to reach 35 ± 7 mmHg on postoperative day 28 vs 18 ± 4 in sham (P = 0.001), likewise the proportion of muscularized distal pulmonary arteries, 83 ± 1% vs 5 ± 1%, respectively (P < 0.001), related to in situ PA-SMC proliferation. The right ventricle area and lateral wall thickness were doubled in the PN group on postoperative day 28. The left ventricle ejection fraction decreased on postoperative days 7 and 28 while the right ventricle function was maintained. In vitro, the human PA-SMC growth was significantly greater when seeded with stretched vs non-stretched P-EC media, highlighting the role of shear stress on the P-EC paracrine function. CONCLUSIONS: Right PN led to pulmonary hypertension and proportional right heart remodelling in rats. The shear stress related to high blood flow alters the pulmonary endothelial paracrine control of SMC growth.

Human mesenchymal stem cells reduce mortality and bacteremia in gram-negative sepsis in mice in part by enhancing the phagocytic activity of blood monocytes.

The potential therapeutic value of cell-based therapy with mesenchymal stem cells (MSC) has been reported in mouse models of polymicrobial peritoneal sepsis. However, the mechanisms responsible for the beneficial effects of MSC have not been well defined. Therefore, we tested the therapeutic effect of intravenous bone marrow-derived human MSC in peritoneal sepsis induced by gram-negative bacteria. At 48 h, survival was significantly increased in mice treated with intravenous MSC compared with control mice treated with intravenous fibroblasts (3T3) or intravenous PBS. There were no significant differences in the levels of TNF-α, macrophage inflammatory protein 2, or IL-10 in the plasma. However, there was a marked reduction in the number of bacterial colony-forming units of Pseudomonas aeruginosa in the blood of MSC-treated mice compared with the 3T3 and PBS control groups. In addition, phagocytic activity was increased in blood monocytes isolated from mice treated with MSC compared with the 3T3 and PBS groups. Furthermore, levels of C5a anaphylotoxin were elevated in the blood of mice treated with MSC, a finding that was associated with upregulation of the phagocytosis receptor CD11b on monocytes. The phagocytic activity of neutrophils was not different among the groups. There was also an increase in alternately activated monocytes/macrophages (CD163- and CD206-positive) in the spleen of the MSC-treated mice compared with the two controls. Thus intravenous MSC increased survival from gram-negative peritoneal sepsis, in part by a monocyte-dependent increase in bacterial phagocytosis.