title: Role of LTB₄ in 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 LTB₄ pathway plays an important role in the pathogenesis of neutrophilic inflammation that contributes to pulmonary emphysema. In this study, significant levels of LTB₄ 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 LTB₄ in the pathogenesis of emphysema, we compared the lungs of wild-type (WT) and LTA₄ hydrolase-/- mice (LTB₄ deficient, LTA₄H-/-) exposed to intranasal elastase or vehicle control. We found that intranasal elastase induced accumulation of LTB₄ in 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 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 LTA₄H-/- mice compared with elastase-exposed WT mice. Together, these findings demonstrated that LTB₄ played an important role in promoting the pathogenesis of pulmonary emphysema associated with neutrophilic pulmonary inflammation.
authors.affiliation: Dept. of Medicine, Univ. of Virginia, Charlottesville, 22908-0546, USA. yss6n@virginia.edu
authors.forename: Y Michael
authors.initials: YM
authors.lastname: Shim
authors.forename: Mikell
authors.initials: M
authors.lastname: Paige
authors.forename: Halim
authors.initials: H
authors.lastname: Hanna
authors.forename: Su H
authors.initials: SH
authors.lastname: Kim
authors.forename: Marie D
authors.initials: MD
authors.lastname: Burdick
authors.forename: Robert M
authors.initials: RM
authors.lastname: Strieter
mesh_terms: D000368:Aged; D000818:Animals; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007975:Leukotriene B4 / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism; D010196:Pancreatic Elastase / Q000494:pharmacology*; D011656:Pulmonary Emphysema / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*
chemical_list: D007975:Leukotriene B4; D004851:Epoxide Hydrolases; D010196:Pancreatic Elastase; C043134:leukotriene A4 hydrolase
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