RESUMO
The histopathology of chronic pulmonary hypertension includes microvascular proliferation and neointimal formation. Nitric oxide (NO) has been implicated in the regulation of these mechanisms, but how NO controls microvascular proliferation and its effect on pulmonary microvascular cells is still unclear. In this study, we characterized the in vitro effects of NO on rat pulmonary microvascular smooth muscle cell (PMVSMC) proliferation and investigated the contribution of the p42/44 mitogen-activated protein kinase (MAPK) pathway and p21(waf1/cip1) induction to this response. NO donors inhibited PMVSMC proliferation in a dose-dependent manner. In the presence of hypoxia, the degree of inhibition was significantly enhanced. This inhibition was reversible and independent of apoptosis. The soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) had no impact on proliferation rates, suggesting a cyclic guanosine monophosphate-independent process. Administration of MEK1/2 inhibitors failed to abrogate the antimitotic effect of NO. There was a two- fold induction of the cyclin-dependent kinase inhibitor p21 in PMVSMC treated with NO donors. Under hypoxic conditions, NO caused a three-fold increase in p21 levels. These results demonstrate that NO inhibits PMVSMC proliferation and that this inhibition is not the result of p42/44 MAPK activation. The ability of NO to induce p21 upregulation may be a mechanism by which it exerts antiproliferative effects in PMVSMC.
Assuntos
Ciclinas/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Doadores de Óxido Nítrico/farmacologia , Circulação Pulmonar/efeitos dos fármacos , Animais , Divisão Celular/efeitos dos fármacos , Hipóxia Celular/fisiologia , Células Cultivadas , GMP Cíclico/fisiologia , Inibidor de Quinase Dependente de Ciclina p21 , Relação Dose-Resposta a Droga , Ativação Enzimática , Masculino , Microcirculação , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Doadores de Óxido Nítrico/administração & dosagem , Compostos Nitrosos/administração & dosagem , Compostos Nitrosos/farmacologia , Ratos , Ratos Sprague-Dawley , S-Nitroso-N-Acetilpenicilamina/administração & dosagem , S-Nitroso-N-Acetilpenicilamina/farmacologia , Regulação para CimaRESUMO
OBJECTIVE: The use of airway stents in the pediatric population is uncommon, reflected in the few patient series reported in the literature. We describe a fatal complication of tracheal stent placement in an 18-month-old child with spondylothoracic dysplasia. DESIGN: Case report. SETTING: Intensive care unit of a tertiary academic pediatric center. PATIENT: An 18-month-old child with spondylothoracic dysplasia who underwent tracheal stent placement for tracheomalacia. INTERVENTIONS: Management of an acute upper-airway hemorrhage. MAIN RESULTS: The patient died, despite aggressive interventions. CONCLUSION: Use of tracheal stents in pediatric patients with tracheomalacia is not without risks; tracheal erosion with severe hemoptysis is an infrequent but devastating complication of this intervention.