Tissue Inhibitor of Metalloproteinases 3 Regulates Resolution of Inflammation following Acute Lung Injury

Tissue inhibitor of metalloproteinases 3 (TIMP3) inhibits not only matrix metalloproteinases but also a disintegrin and metalloproteinase domain family members and thus contributes to controlling diverse processes mediated by proteolysis. We used Timp3(-/-) mice to assess the role of this inhibitor in acute lung injury. After bleomycin-induced injury, inflammation, as indicated by the influx of neutrophils in bronchoalveolar lavage (BAL), peaked at 7 days post-injury in the wild-type mice and began to wane thereafter; however, in Timp3(-/-) mice, inflammation persisted up to 28 days. Furthermore, although the level of chemokines in BAL and lung homogenate was similar in both genotypes, BAL from Timp3(-/-) mice 7, 14, and 28 days post-injury had increased neutrophil chemotactic activity compared with wild-type BAL. At day 14, a higher percentage of apoptotic neutrophils were present in wild-type mice compared with Timp3(-/-) mice, further suggesting that TIMP3 constrains continued neutrophil influx. In addition, total matrix metalloproteinase activity was increased in lungs from Timp3(-/-) mice, and treatment of mice with a synthetic inhibitor of metalloproteinases rescued the enhanced neutrophilia phenotype. These data demonstrate that TIMP3 regulates neutrophil influx in the lung following injury through its ability to inhibit metalloproteinase activity and indicates that TIMP3 functions to promote the resolution of inflammation in the lung. (Am J Pathol 2010, 176:64-73; DOI: 10.2353/ajpath.2010.090158)