Department of Microbiology and Immunology, the Graduate Center for Toxicology, and the Department of Internal Medicine, University of Kentucky, College of Medicine, Lexington, Kentucky
Correspondence: Dr. Alan M. Kaplan, Department of Microbiology and Immunology, University of Kentucky, College of Medicine, 800 Rose Street, Room MS 411, Lexington, KY 40536-0084. E-mail: akaplan{at}pop.uky.edu
Eosinophils have been shown to increase in tissues during many fibrotic
conditions and consequently have been suggested to contribute to the
development of fibrosis. This study tested the hypothesis that
eosinophils are essential in the development of lung fibrosis in mice
in response to bleomycin (BLM). Anti-IL-5 antibody was administered
intraperitoneally into mice 2 h prior to endotracheal BLM
inoculation and thereafter, every other day. Lung eosinophilia was
evaluated by measurement of eosinophil peroxidase activity and
confirmed by eosinophil counts in histologic sections. Lung fibrosis
was evaluated by hydroxyproline content and confirmed by collagen
staining in histological sections. Results demonstrated that BLM
induced pronounced lung eosinophilia, which was maximal 7 days after
BLM treatment and remained elevated through day 14, in C57Bl/6 SCID
mice and CBA/J mice. In contrast, eosinophilia was a minor component in
the lungs of wildtype C57Bl/6 mice after BLM treatment, although lung
fibrosis developed similarly in all three strains of mice. Treatment
with anti-IL-5 completely abrogated eosinophilia but failed to block
pulmonary fibrosis induced by BLM in all mouse strains, including
C57Bl/6 SCID, wildtype C57Bl/6 mice, and CBA/J mice. Analysis of
cytokine mRNA by RNase-protection assay in C57Bl/6 SCID mice indicated
that BLM treatment caused enhanced expression of the cytokines,
TNF-
, and IL-6 at days 3, 7, and 14 post-BLM inoculation, regardless
of whether eosinophils were depleted by anti-IL-5. Finally, the
importance of eosinophils in lung fibrosis was examined in IL-5 gene
knockout mice (IL-5tm1Kopf). BLM treatment induced
significant lung fibrosis in IL-5 knockout mice in the absence of
eosinophilia. These findings indicate that eosinophils are not an
absolute requirement for BLM-induced pulmonary fibrosis in the
mouse.
Key Words: lung eosinophilia • cytokines • knockout mice
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