Macrophage inflammatory protein-1 alpha mediates lung leukocyte recruitment, lung capillary leak, and early mortality in murine endotoxemia.
Systemic exposure to LPS initiates a complex sequence of events resulting in organ-specific leukocyte recruitment and end-organ injury. We hypothesized that macrophage inflammatory protein-1 alpha (MIP-1 alpha), a C-C chemokine with leukocyte chemotactic and activating properties, may play an important role in lung inflammatory cell recruitment, subsequent lung injury, and mortality in endotoxemia. CD-1 mice were challenged with LPS (200 micrograms), resulting in a maximal 3.5-fold increase in neutrophils (polymorphonuclear leukocytes (PMNs)) at 6 h post-LPS, and a 2.6-fold increase in numbers of macrophages (M phi) within lung minces at 24 h. A time-dependent increase in MIP-1 alpha mRNA and protein was detected in lung after LPS treatment, with immunolocalization of MIP-1 alpha to blood and lung M phi, and the subendothelium. The pretreatment of mice with rabbit anti-MIP-1 alpha Ab resulted in a decrease in the influx of PMNs at 6 h, and influx of M phi at 24 h post-LPS challenge, an approximately 65% reduction in LPS-induced lung permeability to Evans blue, and a modest decrease in mortality at 24, but not 48 h post-LPS. Furthermore, passive immunization of mice with anti-MIP-1 alpha serum resulted in a 35% reduction in ICAM-1 mRNA levels within lung homogenates post-LPS. Finally, the pretreatment of animals with sTNFR:Fc (soluble TNF receptor:Ig construct) resulted in a 60% reduction in LPS-induced MIP-1 alpha mRNA expression within lung homogenates at 4 h post-LPS. Our studies indicate that MIP-1 alpha plays an integral role as a mediator of both PMN and M phi recruitment in murine endotoxemia.
Standiford
T J
TJ
Department of Medicine, University of Michigan Medical School, Ann Arbor 48109, USA.
Kunkel
S L
SL
Lukacs
N W
NW
Greenberger
M J
MJ
Danforth
J M
JM
Kunkel
R G
RG
Strieter
R M
RM
D000818:Animals; D001483:Base Sequence; D002199:Capillary Permeability; D054407:Chemokine CCL4; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007106:Immune Sera; D007116:Immunization, Passive; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D019402:Macrophage Inflammatory Proteins; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D015846:Monokines / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009504:Neutrophils / Q000502:physiology; D011654:Pulmonary Edema / Q000209:etiology / Q000503:physiopathology; D012333:RNA, Messenger / Q000096:biosynthesis; D011817:Rabbits; D012772:Shock, Septic / Q000150:complications / Q000503:physiopathology*; D013047:Specific Pathogen-Free Organisms; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D054407:Chemokine CCL4; D016207:Cytokines; D007106:Immune Sera; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1