Adipose triglyceride lipase-mediated lipid catabolism is essential for bronchiolar regeneration.

The lung airways are constantly exposed to inhaled toxic substances, resulting in cellular damage that is repaired by local expansion of resident bronchiolar epithelial club cells. Disturbed bronchiolar epithelial damage repair lies at the core of many prevalent lung diseases, including chronic obstructive pulmonary disease, asthma, pulmonary fibrosis, and lung cancer. However, it is still not known how bronchiolar club cell energy metabolism contributes to this process. Here, we show that adipose triglyceride lipase (ATGL), the rate-limiting enzyme for intracellular lipolysis, is critical for normal club cell function in mice. Deletion of the gene encoding ATGL, Pnpla2 (also known as Atgl), induced substantial triglyceride accumulation, decreased mitochondrial numbers, and decreased mitochondrial respiration in club cells. This defect manifested as bronchiolar epithelial thickening and increased airway resistance under baseline conditions. After naphthalene­induced epithelial denudation, a regenerative defect was apparent. Mechanistically, dysfunctional PPARα lipid-signaling underlies this phenotype because (a) ATGL was needed for PPARα lipid-signaling in regenerating bronchioles and (b) administration of the specific PPARα agonist WY14643 restored normal bronchiolar club cell ultrastructure and regenerative potential. Our data emphasize the importance of the cellular energy metabolism for lung epithelial regeneration and highlight the significance of ATGL-mediated lipid catabolism for lung health.

Relationship between vascular damage degrees and endothelial progenitor cells in patients with erectile dysfunction: effect of vardenafil administration and PDE5 expression in the bone marrow.

OBJECTIVES: To evaluate the levels of circulating progenitor cells (PCs) and the effect of a single dose of vardenafil 20mg on the number of these cells in men with erectile dysfunction (ED) and various degree of vascular injury at the carotid artery level. METHODS: Sixty-eight patients with ED and various degree of carotid damage, and 25 controls were enrolled. Patients were divided into three groups according to their intima media thickness (IMT) status (normal, mild increase, or plaque). All subjects received vardenafil 20mg, and evaluation of the number of circulating PCs was performed at baseline and 4h after vardenafil administration. An RNA expression analysis of phosphodiesterase type 5 (PDE5) on bone marrow was also performed. RESULTS: We found a significant reduction of circulating PCs in ED patients with respect to controls and a reduction in PC counts in patients with mild IMT increase or plaque, but not in those with normal IMT. Four hours after vardenafil administration we observed an increase in the number of PCs in all patients and controls. Reverse transcriptase-polymerase chain reaction analysis showed that human bone marrow expresses PDE5 messenger RNA. CONCLUSIONS: Patients with ED and a low number of circulating PCs may be considered at increased risk for an endothelial dysfunction. An impaired response to vardenafil stimulus may be proposed as a surrogate marker of a patient's endothelial regenerative ability.