The Experimental Research Of Treatment Of Hypoxic Induced Pulmonary Hypertension By Endothelial Progenitor Cell Transplantation Preconditioned By Lysophosphatidic Acid

Hypoxic pulmonary hypertension(HPH)as a cause of pulmonary heart disease seriously threats human health,which is characterized by increased pulmonary artery pressure and resistance with hypoxic induced pulmonary vasoconstriction and abnormal proliferation of smooth muscle cell.Conventional and traditional drugs in treatment of patients with pulmonary arterial hypertension(PAH)are invalid in HPH.Therefore,because of its complex pathogenesis and poor prognosis early diagnosis and reasonable treatment for HPH are particularly important.As a precursor cells of endothelial cells,endothelial progenitor cells(EPCs)play a key role in the formation of blood vessels and repairing.Animal experiments and clinical trials have proved that EPCs transplantation has a good effect on vascular repair.However,there are some problems about EPCs,such as limited amplification in vitro,easy differentiation or low survival after transplantation in vivo.Our previous studies showed that lysophosphatidic acid(LPA)promoted proliferation and migration of EPCs derived from rat bone marrow and LPA pretreatment had the therapeutic effect of EPC with increasing the number of EPCs in lung tissue after transplantation.LPA is endogenous active phospholipid,promoting a variety of cell division,migration and apoptosis through cell membranes of G-protein-coupled receptors(GPCRs).In our research,the pretreatment role and mechanism of LPA in EPCs transplantation in HPH rats are studied.It is proved that EPC transplantation can partially inhibit hypoxic induced HMGB1,TLR4,IL-17 and IL21 expression in pulmonary and peripheral blood and restrain further development of pulmonary hypertension with significantly reducing thickening of pulmonary artery wall,less exfoliating of endothelial cells,reducing the infiltration of inflammatory cells and inflammation.LPA pretreatment can increase EPC number in lung tissue after transplantation,promote inhibition effect of EPC on the expression of HMGB1,TLR4,IL-17 and IL-21 and inhibit the formation of pulmonary hypertension with improving the repair of endothelial cell damage and reducing the infiltration of inflammatory cells.Our study shows that LPA with a very good application value in cell therapy has stem cell protective effect in EPC treatment of HPH and other cardiovascular disease process by promoting EPCs proliferation and migration activity and regulating inflammatory response.