Production and function of murine macrophage inflammatory protein-1 alpha in bleomycin-induced lung injury.
We investigated the role of macrophage inflammatory protein-1 alpha (MIP-1 alpha) in bleomycin-induced lung injury, a model of interstitial lung disease. Bleomycin stimulates a T cell-dependent pulmonary inflammatory response characterized by an increase in leukocyte infiltration, fibroblast proliferation, and collagen synthesis. Intratracheal challenge of CBA/J mice with bleomycin resulted in a significant time-dependent increase in MIP-1 alpha protein levels both in whole-lung homogenates and bronchoalveolar lavage fluid. The kinetics of MIP-1 alpha expression were biphasic, with the first peak occurring at 2 days postinstillation and the second peak at 16 days. These levels of Ag expression temporally correlated with the accumulation of granulocytes, lymphocytes, and mononuclear phagocytes in the lung. In addition, immunohistochemical staining identified alveolar macrophages and bronchial epithelial cells as the primary cellular sources of MIP-1 alpha production. Interestingly, passive immunization of bleomycin-challenged mice with anti-MIP-1 alpha Abs significantly reduced pulmonary mononuclear phagocyte accumulation and fibrosis. These experiments establish that MIP-1 alpha protein is expressed in the lungs of bleomycin-treated mice and provide evidence that MIP-1 alpha promotes leukocyte accumulation and activation. Furthermore, these findings support the notion that leukocyte accumulation and activation are linked to fibrosis.
Smith
R E
RE
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109.
Strieter
R M
RM
Phan
S H
SH
Lukacs
N W
NW
Huffnagle
G B
GB
Wilke
C A
CA
Burdick
M D
MD
Lincoln
P
P
Evanoff
H
H
Kunkel
S L
SL
D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D001992:Bronchoalveolar Lavage Fluid; D054407:Chemokine CCL4; D016207:Cytokines / Q000096:biosynthesis / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D006909:Hydroxyproline / Q000032:analysis; D007116:Immunization, Passive; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology; D008171:Lung Diseases / Q000139:chemically induced* / Q000276:immunology* / Q000473:pathology; D019402:Macrophage Inflammatory Proteins; D051379:Mice; D008808:Mice, Inbred CBA; D015846:Monokines / Q000096:biosynthesis / Q000502:physiology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology
D054407:Chemokine CCL4; D016207:Cytokines; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D001761:Bleomycin; D006909:Hydroxyproline