Role of LTB4in the pathogenesis of elastase-induced murine pulmonary emphysema

Abstract

Exaggerated levels of the leukotriene B4(LTB4) frequently coexist at sites of inflammation and tissue remodeling. Therefore, we hypothesize that the LTB4pathway plays an important role in the pathogenesis of neutrophilic inflammation that contributes to pulmonary emphysema. In this study, significant levels of LTB4were detected in human lung tissues with emphysema compared with lungs without emphysema (9,497 ± 2,839 vs. 4,142 ± 1,173 pg/ml, n = 9 vs. 10, P = 0.04). To further determine the biological role of LTB4in the pathogenesis of emphysema, we compared the lungs of wild-type (WT) and LTA4hydrolase−/− mice (LTB4deficient, LTA4H−/−) exposed to intranasal elastase or vehicle control. We found that intranasal elastase induced accumulation of LTB4in the lungs and caused progressively worsening emphysema between 14 and 28 days after elastase exposure in WT mice but not in LTA4H−/− mice. Premortem physiology documented increased lung compliance in elastase-exposed WT mice compared with elastase-exposed LTA4H−/− mice as measured by Flexivent (0.058 ± 0.005 vs. 0.041 ± 0.002 ml/cmH2O pressure). Postmortem morphometry documented increased total lung volume and alveolar sizes in elastase-exposed WT mice compared with elastase-exposed LTA4H−/− mice as measured by volume displacement and alveolar chord length assessment. Furthermore, elastase-exposed LTA4H−/− mice were found to have significantly delayed influx of the CD45highCD11bhighLy6Ghighleukocytes compatible with neutrophils compared with elastase-exposed WT mice. Mechanistic insights to these phenotypes were provided by demonstrating protection from elastase-induced murine emphysema with neutrophil depletion in the elastase-exposed WT mice and by demonstrating time-dependent modulation of cysteinyl leukotriene biosynthesis in the elastase-exposed LTA4H−/− mice compared with elastase-exposed WT mice. Together, these findings demonstrated that LTB4played an important role in promoting the pathogenesis of pulmonary emphysema associated with neutrophilic pulmonary inflammation.