Abstract
Acute lung injury (ALI) is a major cause of respiratory failure in the critically ill patient. With a mortality rate of 40-60%, 50% of survivors left with pulmonary impairment and no current licenced treatment there is a need for novel therapies. Our current research suggests that local steroid metabolism by alveolar macrophages is defective in ALI patients. As a major function of these cells is phagocytosis of apoptotic neutrophils during resolution of inflammation, we sought to investigate the effect of pre-receptor glucocorticoid metabolism in a murine model of ALI.
Using intra-tracheal instillations of LPS, we analysed the inflammatory response in wildtype mice compared to those deficient in 11β-hydroxysteroid dehydrogenase 1 (HSD1). These mice specifically lack the enzyme which converts inactive cortisone to active cortisol. Cell infiltrates and expression of several inflammatory markers within bronchial lavage fluid, as well as tissue permeability were examined to evaluate the immune response and lung damage.
Here we report that in HSD1-/- mice, lung permeability increases (6.1x10-3 ±0.9x10-3 v 10.7x10-3 ±2x10-3) 24hrs post-LPS. In addition, there was a build-up of apoptotic neutrophils (20.3x103 ±5.9x103 v 39.2x103 ±6.1x103), with a significant increase in CD11c+CD11b+ monocytes recruited into the lung (35.2x103 ±5.7x103 v 81.8x103 ±1.4x103) 72hrs post-LPS. Moreover, dys-regulation of IL6 was observed (1.5ng/ml ±0.62 versus 0.2ng/ml ±0.08) 72hrs post-LPS.
Our data indicate that insufficient alveolar glucocorticoid metabolism augments lung injury and suggests that therapies targetting defective macrophage HSD-1 expression may have value in ALI.
- © 2012 ERS