Phosphatidylethanolamine Induces an Antifibrotic Phenotype in Normal Human Lung Fibroblasts and Ameliorates Bleomycin-Induced Lung Fibrosis in Mice.

Lung surfactant is a complex mixture of phospholipids and specific proteins but its role in the pathogenesis of interstitial lung diseases is not established. Herein, we analyzed the effects of three representative phospholipid components, that is, dipalmitoilphosphatidylcoline (DPPC), phosphatidylglycerol (PG) and phosphatidylethanolamine (PE), on collagen expression, apoptosis and Ca2+ signaling in normal human lung fibroblasts (NHLF) and probed their effect in an experimental model of lung fibrosis. Collagen expression was measured with RT-PCR, apoptosis was measured by using either the APOPercentage assay kit (Biocolor Ltd., Northern Ireland, UK) or the Caspase-Glo 3/7 assay (Promega, Madison, WI, USA) and Ca2+ signaling by conventional epifluorescence imaging. The effect in vivo was tested in bleomycin-induced lung fibrosis in mice. DPPC and PG did not affect collagen expression, which was downregulated by PE. Furthermore, PE promoted apoptosis and induced a dose-dependent Ca2+ signal. PE-induced Ca2+ signal and apoptosis were both blocked by phospholipase C, endoplasmic reticulum pump and store-operated Ca2+ entry inhibition. PE-induced decrease in collagen expression was attenuated by blocking phospholipase C. Finally, surfactant enriched with PE and PE itself attenuated bleomycin-induced lung fibrosis and decreased the soluble collagen concentration in mice lungs. This study demonstrates that PE strongly contributes to the surfactant-induced inhibition of collagen expression in NHLF through a Ca2+ signal and that early administration of Beractant enriched with PE diminishes lung fibrosis in vivo.

El miofibroblasoo, una célula multifuncional en la patología pulmonar

Los miofibroblastos representan una subpoblación de fibroblastos con un fenotipo similar al de las células del músculo liso, debido a que expresan a-actina de músculo liso en su citoesqueleto, aunque también como subpoblación exhiben diferencias fenotípicas entre sí en diferentes órganos, su fisiología es semejante en los diferentes tejidos y órganos en que se encuentren. Con base en su amplio espectro de síntesis y secreción de moléculas, tales como citocinas, interleucinas, quimiocinas, factores del crecimiento, lípidos, diversos mediadores fisiológicos, moléculas de la matriz extracelular, MMPs y TIMPs, desempeñan una participación muy importante durante la embriogénesis, organogénesis, inflamación, reparación y cicatrización, siendo además fundamentales en los diferentes procesos de regeneración y reparación (fibrosis) que ocurren en los distintos órganos. En el caso del sistema respiratorio, los miofibroblastos son importantes, tanto en las vías aéreas como en el pulmón, participando fundamentalmente en los diversos procesos patogénicos, ya sea en enfermedades con un patrón degradativo como el enfisema, o bien, con un patrón reparativo con depósito excesivo de los diversos componentes de la matriz extracelular, tal como ocurre en la fibrosis pulmonar y el asma. Son especialmente importantes en las diferentes formas de fibrosis pulmonar ya sea de causa conocida o idiopática. Esta última, a semejanza del asma, parece restringirse fundamentalmente a zonas del tejido adyacente a epitelios alveolares dañado, donde se da una relación fisiopatogénica neumocito tipo II-miofibroblasto-fibroblasto. Los miofibroblastos se originan principalmente por transdiferenciación de fibroblastos y principalmente por estimulación del TGF-β1.

Myofibroblasts are a fibroblast subpopulation with a phenotype similar to smooth muscle cells, since they express the cytoskeletal a-smooth muscle actin (α-SMA); however, in different organs, they show some phenotypical differences. Their physiology is similar in the different tissues and organs. Based on their extensive spectrum of synthesis and secretion of molecules such as cytokines, interleukins, chemokines, growth factors, lipids, diverse physiological mediators, molecules of the extracelullar matrix, MMPs and TIMPs, they play a very important role during embryogenesis, organogenesis, inflammation, repair and wound healing, besides being fundamental in the processes of regeneration and repair (fibrosis) that occur in the different organs. In the case of the respiratory system, the myofibroblasts are as important in the air ways as in the lung, mainly participating in the diverse pathogenic processes; whether in pathologies with a derivative pattern such as emphysema, or in diseases with a fibrogenic pattern with excessive synthesis of the diverse components of the extracellular matrix, as occurs in pulmonary fibrosis and asthma. Myofibroblasts are especially important in the different forms of pulmonary fibrosis whether idiopathic or of known cause. Idiopathic fibrosis, as asthma, seems to be essentially restricted to areas of tissue adjacent to damaged alveolar-epithelial areas, where a physiopathogenic relation of type II neumocyte-myofibroblast-fibroblast exists. On the other hand, myofibroblasts are mostly derived from fibroblast transdifferentiation by TGF-β1 stimulation.