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.
Shanley
T P
TP
Division of Critical Care Medicine, Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA.
Davidson
B A
BA
Nader
N D
ND
Bless
N
N
Vasi
N
N
Ward
P A
PA
Johnson
K J
KJ
Knight
P R
PR
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