Effect Of Surfactant On Pulonary Homeostasis In The Mice

Pulmonary surfactant deficiency/malfunction is the main cause of neonatal respiratory distress syndrome. Secreted by alveolar type II epithelial cells, pulmonary surfactant consists of 5%-10% surfactant proteins and 80%-90% phospholipids, which are essential for protecting the lung from the collapse by lowering tension at the air-liquid interface, and for maintaining normal lung function in various physiological conditions and host defenses. Still, pulmonary surfactant consists of 5%-10% neutral lipids, the functional roles of which are poorly understood in the lung. Lysosomal acid lipase (LAL) is one of the lysosomal hydrolases which hydrolyze most important components in neutral lipids, such as cholesteryl ester and triglycerides. In the present study, one LAL gene knock out mice model (lal-/-) was utilized to assess physiological consequences after the neutral lipids metabolic pathways in the lung were blocked; Affymetrix GeneChip microarray analysis was conducted to elucidate the mechanism underlining these pathogenesis. Since many neutral lipid metabolites serve as ligands for nuclear receptors, such as peroxisome proliferator activated receptor (PPARγ), intranasal treatment of lal-/- mice with natural occurring and synthetic PPARγ ligands was conducted to observe the potential role of this pathway. The results demonstrated that blocking neutral lipids metabolism in the lal-/- mice resulted in severe age dependent chronic respiratory inflammation: massive neutrophil infiltration; foamy macrophage accumulation; unwanted remodeling of the alveolar structure, pulmonary emphysema, and Clara cell hypertrophy and hyperplasia. Consisted with these pathogenic phenotypes, Affymetrix GeneChip microarray analysis of 1, 3 and 6 month old mice identified aberrant gene expression with age progression. Among them are proinflammatory cytokines/chemokines, matrix metalloproteinase 8, 9 and 12, apoptosis inhibitor 6, erythroblast transformation-specific domain (ETS) transcription factor family member SpiC and oncogene MafB. Treatment of 9-hydroxyoctadecanoic acids (9-HODE) and ciglitazone significantly rescued lal-/- pulmonary inflammation and aberrant gene expression. These studies support the concept that neutral lipids in the pulmonary surfactant play essential roles in pulmonary homeostasis and host defense. The pathological consequences after blocking the neutral lipids metabolism are partially caused by inactivation of PPARγ pathway.