Similar articles

Abstract: Objective: To investigate the evolution of pulmonary hypertension, the pathological changes of pulmonary arteries, and the expression of VEGFmRNA and eNOSmRNA of pulmonary arterial endothelial cells in immature rabbits treated with intratracheal bleomycin (BLM). Methods: Immature rabbits were divided into control and BLM group. Two and four weeks after intratracheal normal saline or BLM injection, the systolic, diastolic and mean pulmonary artery pressure (PASP, PADP, MPAP) were measured by micro-catheter; the pathological changes and the expression of VEGFmRNA and eNOSmRNA of endothelial cells in pulmonary arteries were evaluated by HE and in situ hybridization. Results: Two and four weeks after intratracheal injection of BLM, the PASP, PADP and MPAP increased 53%, 49%, 52% in 2 weeks, and 43%, 89%, 56% in 4 weeks; the wall thickness increased and the cavity in middle and small pulmonary arteries became narrow; the Thickness Index (TI) and Area Index (AI) increased 25%, 14% in 2 weeks, and 22%, 24% in 4 weeks; the level of VEGFmRNA and eNOSmRNA expression decreased 46%, 43% in 2 weeks, and 43%, 51% in 4 weeks. There was no significant difference between 2 weeks and 4 weeks BLM groups. Conclusion: The pulmonary artery pressure was elevated, the thickness of wall increased and the cavity became narrow in middle and small pulmonary arteries, and the level of VEGFmRNA and eNOSmRNA expression in pulmonary arterial endothelial cells decreased in immature rabbits after 2 weeks and 4 weeks of intratracheal 4 U/kg BLM injection.

[1] Assender, J.W., Southgate, K.M., Newby, A.C., 1991. Does nitric oxide inhibit smooth muscle cell proliferation? J Cardiovasc Pharmacol, 17:104-107.

[2] Bishop, J.E., Guerreiro, D., Laurent, G.J., 1990. Changes in the composition and metabolism of arterial collagens during the development of pulmonary hypertension in rabbits. Am Rev Respir Dis, 141:450-455.

[3] Champion, H.C., Bivalacqua, T.J., D’Souza, F.M., Ortiz, L.A., Jeter, J.R., Toyoda, K., Heistad, D.D., Hyman, A.L., Kadowitz, P.J., 1999. Gene transfer of endothelial nitric oxide synthase to the lung of the mouse in vivo. Effect on agonist-induced and flow-mediated vascular responses. Circ Res, 84:1422-1432.

[4] Chung, M.P., Monick, M.M., Hamzeh, N.Y., Butler, N.S., Powers, L.S., Hunninghake, G.W., 2003. Role of repeated lung injury and genetic background in bleomycin-induced fibrosis. Am J Respir Cell Mol Biol, 29:375-80.

[5] deGraaf, J.C., Banga, J.D., Moncada, S., Palmer, R.M., de Groot, P.G., Sixma, J.J., 1992. Nitric oxide functions as an inhibitor of platelet adhesion under flow conditions. Circulation, 85:2284-2290.

[6] Faraci, F.M., Brian, J.F. Jr., 1994. Nitric oxide and the cerebral circulation. Stroke, 25:692-703.

[7] Fehrenbach, H., Haase, M., Kasper, M., Koslowski, R., Schuh, D., Muller, M., 1999. Alterations in the immunohistochemical distribution patterns of vascular endothelial growth factor receptors Flk1 and Flt1 in bleomycin-induced rat lung fibrosis. Virchows Arch, 435:20-31.

[8] Ferrara, N., Henzel, W.J., 1989. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem. Biophys Res Commun, 161:851-858.

[9] Garg, U.C., Hassid, A., 1989. Nitric oxide generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest, 83:1774-1777.

[10] Heath, D., 1993. The pathology of pulmonary hypertension. Eur Respir Rev, 3:555-558.

[11] Leung, D.W., Cachianes, G., Kuang, W.J., Goeddel, D.V., Ferrara, N., 1989. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science, 246:1306-1309.

[12] Michel, R.P., Hakim, T.S., Freeman, C.R., 1988. Distribution of pulmonary vascular resistance in experimental fibrosis. J Appl Physiol, 65:1180-1190.

[13] Moncada, S., Higgs, E.A., 1993. The L-arginine-nitric oxide pathway. N Engl J Med, 329:2002-2012.

[14] Moncada, S., Palmer, R.M.J., Higgs, E.A., 1991. Nitric oxide: physiology, pathology, and pharmacology. Pharmacol Rev, 43:109-142.

[15] Phan, S.H., Thrall, R.S., Williams, C., 1981. Bleomycin-induced pulmonary fibrosis. Effects of steroid on lungcollagen metabolism. Am Rev Respir Dis, 124:428-434.

[16] Plate, K.H., Breier, G., Weich, H.A., Mennel, H.D., Risau, W., 1992. Vascular endothelial growth factor is a potential tumor angiogenesis factor in vivo. Nature, 359:845-847.

[17] Radomski, M.W., Palmer, R.M.J., Moncada, S., 1987. The role of nitric oxide and cGMP in platelet adhesion to vascular endothelium. Biochem Biophys Res Commun, 148:1482-1489.

[18] Roberts, J.D.Jr., Roberts, C.T., Jones, R.C., Zapol, W.M., Bloch, K.D., 1995. Continuous nitric oxide inhalation reduces pulmonary arterial structural changes, right ventricular hypertrophy, and growth retardation in the hypoxic newborn rat. Circ Res, 76:215-222.

[19] Snider, G.L., 1983. Unraveling pulmonary fibrosis-which cell is the culprit? Am Rev Respir Dis, 127:535-539.

[20] Voelkel, N.F., Tuder, R.M., 1995. Cellular and molecular mechanisms in the pathogenesis of severe pulmonary hypertension. Eur Respir J, 8:2129-2138.

[21] Williams, J.H. Jr., Bodell, P., Hosseini, S., Tran, H., Baldwin, K.M., 1992. Haemodynamic sequelae of pulmonary fibrosis following intratracheal bleomycin in rats. Cardiovasc Res, 26:401-408.