Abstract
Exaggerated levels of the leukotriene B&sub4; (LTB&sub4;) frequently coexist at sites of inflammation and tissue remodeling. Therefore, we hypothesize that the LTB&sub4; pathway plays an important role in the pathogenesis of neutrophilic inflammation that contributes to pulmonary emphysema. In this study, significant levels of LTB&sub4; were 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 LTB&sub4; in the pathogenesis of emphysema, we compared the lungs of wild-type (WT) and LTA&sub4; hydrolase-/- mice (LTB&sub4; deficient, LTA&sub4;H-/-) exposed to intranasal elastase or vehicle control. We found that intranasal elastase induced accumulation of LTB&sub4; in the lungs and caused progressively worsening emphysema between 14 and 28 days after elastase exposure in WT mice but not in LTA&sub4;H-/- mice. Premortem physiology documented increased lung compliance in elastase-exposed WT mice compared with elastase-exposed LTA&sub4;H-/- mice as measured by Flexivent (0.058 ± 0.005 vs. 0.041 ± 0.002 ml/cmH&sub2;O pressure). Postmortem morphometry documented increased total lung volume and alveolar sizes in elastase-exposed WT mice compared with elastase-exposed LTA&sub4;H-/- mice as measured by volume displacement and alveolar chord length assessment. Furthermore, elastase-exposed LTA&sub4;H-/- mice were found to have significantly delayed influx of the CD45(high)CD11b(high)Ly6G(high) leukocytes 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 LTA&sub4;H-/- mice compared with elastase-exposed WT mice. Together, these findings demonstrated that LTB&sub4; played an important role in promoting the pathogenesis of pulmonary emphysema associated with neutrophilic pulmonary inflammation.