RESUMEN
The mechanism(s) involved in the development of pulmonary hypertension (PH) in COPD is still the object of investigation. Cigarette smoke (CS) may lead to remodelling of intrapulmonary vessels and dynamic changes in vascular function, at least in some smokers. A role for proteases in PH has been recently put forward. We investigated, in smoking mice, the role of protease-activated receptor (PAR)-2 in the pathogenesis of PH associated with emphysema. We demonstrated that CS exposure can modulate PAR-2 expression in mouse lung. Acute CS exposure induces in wildtype (WT) and in transgenic mice over-expressing PAR-2 (FVB(PAR-2-TgN)) a similar degree of neutrophil influx in bronchoalveolar lavage fluids. After chronic CS exposure WT and FVB(PAR-2-TgN) mice show emphysema, but only transgenic mice develop muscularisation of small intrapulmonary vessels that precedes the development of PH (~45% increase) and right ventricular hypertrophy. Smoking in FVB(PAR-2-TgN) mice results in an imbalance between vasoconstrictors (especially endothelin-1) and vasodilators (i.e. vascular endothelial growth factor, endothelial nitric oxide synthase and inducible nitric oxide synthase) and enhanced production of growth factors involved both in fibroblast-smooth muscle cell transaction (i.e. platelet-derived growth factor (PDGF) and transforming growth factor ß) and vascular cell proliferation (PDGF). PAR-2 signalling can influence the production and release of many factors, which may play a role in the development of PH in smokers.
Asunto(s)
Hipertensión Pulmonar/etiología , Receptor PAR-2/biosíntesis , Fumar/efectos adversos , Animales , Apoptosis , Líquido del Lavado Bronquioalveolar , Proliferación Celular , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Hipertensión Pulmonar/metabolismo , Hipertrofia Ventricular Derecha , Inmunohistoquímica/métodos , Pulmón/efectos de los fármacos , Ratones , Ratones Transgénicos , ARN/metabolismo , Transducción de SeñalRESUMEN
The role of the anti-phospholipid antibodies (APLA) and anti-endothelial cell antibodies (AECA) in the pathogenesis of anti-phospholipid syndrome (APS) is unclear. Differences in the reported involvement of APLA may be due, in part, to the polyclonal nature of these antibodies and the use of serum and serum fractions for analysis. To circumvent this issue, we generated monoclonal antibodies (MAB) from three patients with APS and two healthy controls. We then compared the antigen binding patterns and the heavy chain variable region (VH) DNA sequences of the MAB derived from patients with APS to those from healthy controls. The results of this study indicate that APLA and AECA comprise a highly heterogeneous population of antibodies with respect to the antigens they recognize, as well as VH gene usage. MAB derived from patients with APS do not differ from those derived from normal individuals based on either antigen recognition or VH gene usage. These results suggest the importance of additional predisposing factors in the pathogenesis of APS.