Role of macrophage inflammatory protein-2 in aspiration-induced lung injury.
OBJECTIVE
To determine the role of the chemokine, macrophage inflammatory protein (MIP)-2, in the pathogenesis of aspiration-induced lung injury in the rat.


METHODS
Prospective, randomized, controlled animal study.


METHODS
University research laboratories.


METHODS
Adult, male Long-Evans rats.


METHODS
Anesthetized rats underwent induction of lung injury by well-described models of aspiration triggered by intra-tracheal delivery of acid alone, gastric particles alone, or the combination. After injury, induction of MIP-2 messenger RNA in whole lungs and immunoreactive MIP-2 in bronchoalveolar lavage (BAL) fluids was determined. The contribution of MIP-2 to BAL fluid chemotactic activity was defined by using an in vitro chemotaxis assay. The in vivo effect of blocking MIP-2 on pulmonary vascular leak, BAL fluid neutrophils, PaO2/FIO2 ratio, and alveolar-arterial oxygen tension gradient in acid-induced lung injury was determined.


RESULTS
Induction of MIP-2 messenger RNA and protein over time was observed in response to all three stimuli. A significant portion (25% to 41%) of the chemotactic activity in BAL fluids from injured rats was inhibited by anti-MIP-2 antibody. After acid injury, blocking of MIP-2 was associated with a 53% decrease in BAL fluid neutrophils and a 33% decrease in pulmonary vascular leak. Although acid injury both impaired oxygenation and increased venous admixture, in vivo blocking of MIP-2 was associated with improved oxygenation as well as decreased venous admixture.


CONCLUSIONS
MIP-2 was up-regulated during the development of aspiration-induced lung injury in rats. MIP-2 contributed to lung accumulation of neutrophils via a chemotactic mechanism. Although oxygenation and venous admixture are worsened by acid-induced lung injury in vivo, blocking of MIP-2 at the onset of injury improved these physiologic alterations. Because the aspiration event often is witnessed, chemokines may be valid therapeutic targets for inhibiting the subsequent inflammatory response.
Division of Critical Care Medicine, Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA.
T P
TP
Shanley
B A
BA
Davidson
N D
ND
Nader
N
N
Bless
N
N
Vasi
P A
PA
Ward
K J
KJ
Johnson
P R
PR
Knight
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002630:Chemotactic Factors / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D006851:Hydrochloric Acid / Q000008:administration & dosage; D001239:Inhalation; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages; D008297:Male; D009504:Neutrophils / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020318:Rats, Long-Evans; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation
D002630:Chemotactic Factors; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger; D006851:Hydrochloric Acid