Article Text


Regulating inflammation in acute lung injury
S54 The Role of Pre-Receptor Glucocorticoid Metabolism in Regulating the Severity and Persistence of Murine Lung Injury
  1. S Lax1,
  2. MR Wilson2,
  3. M Takata2,
  4. P Stewart1,
  5. D Thickett1
  1. 1The University of Birmingham, Birmingham, UK
  2. 2Imperial College London, London, UK


Introduction 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 the predominant function of these cells is phagocytosis of apoptotic neutrophils during resolution of inflammation, we sort to investigate the effect of pre-receptor glucocorticoid metabolism in a murine model of ALI

Methods Using intra-tracheal instillations of LPS (50µg), we analysed the inflammatory response in wild type (WT) mice compared to those deficient in 11β-hydroxysteroid dehydrogenase-1 (HSD-1 KO). 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 (BALF), as well as tissue permeability and mouse oximetry were examined to evaluate the immune response and lung damage.

Results Intra-tracheal LPS challenge in WT mice induced a significant increase in lung permeability (p=0.0153), infiltrating neutrophils (p=0.0121) and recruitment of CD11c+CD11b+ monocytes (p<0.0001), which was associated with significant hypoxia (p<0.0001) compared to PBS-treated controls 48hrs post-instillation. The severity of acute neutrophilic inflammation and epithelial barrier defects as measured by lung permeability index were similar in WT and HSD-1 KO mice.

In contrast, during resolution of LPS-induced injury (72 hrs post-instillation), HSD-1 KO mice had a significant accumulation of apoptotic neutrophils (p=0.02) and a significant increase in CD11c+CD11b+ monocytes (p=0.0007) recruited into the lung compared to WT controls. Moreover, Luminex arrays revealed a significant increase in BALF levels of IL-1β (p=0.003) and dysregulation of IL-6, TNFα and CXCL1/KC during the time course.

Conclusion Our data indicate that insufficient alveolar glucocorticoid metabolism augments the duration but not initial severity of lung injury, possibly via a dysregulation of apoptotic neutrophil clearance and suggests that therapies targeting defective macrophage HSD-1 expression may have value in promoting the resolution of ALI.

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