Myofibroblastic activation in vascular remodeling of experimental pulmonary hypertension: its modulation by cellular therapy

• Grant number: 13/21623-6
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: February 01, 2014
• End date: January 31, 2015
• Field of knowledge: Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
• Principal Investigator: Alexandre Todorovic Fabro
• Grantee: Lui Perdoná Rodrigues da Silva
• Host Institution: Hospital das Clínicas. Faculdade de Medicina (FMB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil

Abstract

Pulmonary arterial hypertension (PAH) is a complex, progressive and fatal vascular lung disease characterized by increased pulmonary artery pressure greater than 25 mmHg. Despite considerable and recent advances in understanding and medical therapy for PAH, the 1-year incident mortality rate of PAH remains high (15%). That is the result of the current therapy may not often recover the severe functional and morphological changes in pulmonary vascular lung remodeling, such as medial hypertrophy, concentric laminar intimal fibrosis, fibrinoid degeneration, perivascular inflammation and plexifom lesion. Several experimental PAH models, inclunding monocrotaline- and hypoxia-induced PAH, have demonstrated a complex vascular interaction of and molecular signaling pathways between the pulmonary artery endothelial cells (PAEC) and pulmonary arteries smooth muscle cells (PASMC) in PAH. However, the role of myofibroblasts (MFB) of adventitia has recently been highlighted in the literature. The molecular and pathophysiological mechanisms of PAH go on arterial stiffening, which may cause decreased vascular compliance, worsening of blood flow dynamics and consequently maintenance of PAH. This activation may be the key point of the perpetuation of PAH, being triggered by different factors of vascular injury in experimental models of PAH as the initial lesion of PAEC by monocrotaline and PASMC by hypoxia. The reversal of the myofibroblast activation has been induced by cellular therapy in experimental studies of several lung diseases, for example regenerating pulmonary emphysema, pulmonary vascular remodeling change, reducing chronic inflammation in asthma, improving acute lung injury and reducing asbestos- and irradiation-induced pulmonary fibrosis. Therefore, mesenchymal stem cells have a high therapeutic potential in lung diseases, however the pathophysiological mechanisms and molecular pathways of these therapeutic effects are not well elucidated, what not allowing their modulation for new treatment. In this context, we hypothesized that several pathophysiological mechanisms may be triggered to result in the myofibroblastic activation of adventitial layer for different molecular signaling pathways, leading to their migration and extracellular matrix production. These events cause vascular remodeling by stiffening and vascular thickening, worsening PAH and generating consequently greater remodeling and clinical-morphological changes compatible with pulmonary arterial hypertension. However should be inhibited or actively reversed in situ by mesenchymal stem cells treatment in the pulmonary vasculature by action of its paracrine effect on interstitial microenvironment of adventitia. To investigate in vivo and in situ myofibroblast activation and production profile of type I, III and V collagens, we will use a panel of markers by triple immunofluorescence. This will allow us to quantify them morphometrically in 3 vascular layers and based on arteriolar diameter, and also study them temporally after induction of PAH by monocrotaline and hypoxia with or without cell therapy. (AU)