(CHEST 1999; 116:17S-18S)
Polymorphonuclear leukocytes (PMNs) contain gelatinase B, a matrix metalloproteinase that is readily released from these cells upon stimulation with a variety of agents. Because gelatinase B degrades basement membrane components, and because inhibition of matrix metalloproteinase activity blunts PMN migration through basement membrane in vitro, gelatinase B may be required for PMN emigration in the lung and other tissues. High levels of gelatinase B have been reported in BAL fluid in ARDS patients, raising the possibility that gelatinase B contributes to the pathophysiology of ARDS.
To test whether gelatinase B is necessary for PMN emigration in the lung and to determine the role of gelatinase B in acute lung injury, we studied mice containing a targeted deletion in the gelatinase B gene. Following intratracheal instillation of lipopolysaccharide (LPS), we found that the lung content of PMNs, as determined by myeloperoxidase activity, increased similarly in gelatinase B-deficient and wild-type mice at 3, 6, and 12 h. In addition, BAL fluid contained equivalent numbers of PMNs in both types of mice at 24 h. Alveolar permeability and basement membrane injury were also similar in gelatinase B-deficient mice and wild-type mice, determined by lavage fluid protein concentration as well as the presence of proteolytic fragments of the basement membrane protein entactin in lavage fluid. Moreover, the lungs from deficient and wild-type mice showed the same histopathology by light microscopy after intratracheal LPS.
To determine whether gelatinase B deficiency affects PMN accumulation in tissues other than the lung, we induced acute inflammation in the peritoneal cavity and the skin. No differences were detected between gelatinase B-deficient mice and wild-type mice in the number of PMNs in peritoneal lavage fluid 4 h after thioglyeolate-induced peritonitis or the myeloperoxidase activity of skin 2, 6, 8, and 12 h after an intradermal injection of interleukin-8. Consistent with these observations, we observed that gelatinase B-deficient PMNs migrated through Matrigel-coated micropore membranes in response to zymosan-activated rat serum with the same efficiency as wild-type PMN.
These findings indicate that gelatinase B is not required for PMN emigration in the lung or other tissues and that LPS-induced acute lung injury occurs in the absence of gelatinase B.
(*) From the Pulmonary and Critical Care Medicine Division, Washington University School of Medicine (Drs. Betsuyaku, Shipley, and Senior), St. Louis, MO, and the Department of Dermatology, Medical College of Wisconsin (Dr. Liu), Milwaukee, WI.
Supported by the National Institutes of Health. Dr. Betsuyaku is a Fellow of the Japan Society for the Promotion of Science for Young Scientists. Dr. Shipley is a Parker B. Francis Fellow.
Correspondence to Tomoko Betsuyaku, MD, Pulmonary and Critical Care Medicine, Barnes Jewish Hospital, 216 S Kingshighway Blvd, St. Louis, MO 63110
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