title: Kinetics and Role of Plasma Matrix Metalloproteinase-9 Expression in Acute Lung Injury and the Acute Respiratory Distress Syndrome.
abstract: Primed neutrophils that are capable of releasing matrix metalloproteinases (MMPs) into the circulation are thought to play a significant role in the pathophysiology of acute respiratory distress syndrome (ARDS). We hypothesized that direct measurement of plasma MMP-9 activity may be a predictor of incipient tissue damage and subsequent lung injury, which was investigated in both an animal model of ARDS and a small cohort of 38 critically ill human patients. In a mouse model of ARDS involving instillation of intratracheal lipopolysaccharide (LPS) to induce lung inflammation, we measured neutrophil-mediated inflammation, along with MMP-9 activity in the airways and lung tissue and MMP-9 expression in the plasma. Neutrophil recruitment, inflammation, and MMP-9 activity in the airways and lung tissue increased throughout the 72 h after LPS instillation, whereas plasma MMP-9 expression was greatest at 12 to 24 h after LPS instillation. The results suggest that the peak in plasma MMP-9 activity may precede the peak of neutrophil inflammation in the airways and lung tissue in the setting of ARDS. Based on this animal study, a retrospective observational cohort study involving 38 patients admitted to a surgical intensive care unit at a tertiary care university hospital with acute respiratory failure requiring intubation and mechanical ventilation was conducted. Plasma samples were collected daily, and MMP-9 activity was compared with lung function as determined by the PaO2/FiO2 ratio. In patients who developed ARDS, a notable increase in plasma MMP-9 activity on a particular day correlated with a decrease in the PaO2/FiO2 ratio on the following day (r = -0.503, P < 0.006). Taken together, these results suggest that plasma MMP-9 activity changes, as a surrogate for primed neutrophils may have predictive value for the development of ARDS in a selected subset of critically ill patients.
authors.affiliation: *Department of Biology, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; †Department of Surgery, ‡Division of Translational Research, §Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and ∥Department of Biological Engineering, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute for Technology, Cambridge, Massachusetts.
authors.forename: Albert T
authors.initials: AT
authors.lastname: Hsu
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Barrett
authors.forename: George M
authors.initials: GM
authors.lastname: DeBusk
authors.forename: Christian D
authors.initials: CD
authors.lastname: Ellson
authors.forename: Shiva
authors.initials: S
authors.lastname: Gautam
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Talmor
authors.forename: Diana C
authors.initials: DC
authors.lastname: Gallagher
authors.forename: Michael B
authors.initials: MB
authors.lastname: Yaffe
mesh_terms: D055371:Acute Lung Injury / Q000097:blood / Q000201:enzymology*; D000328:Adult; D000368:Aged; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D016638:Critical Illness; D004195:Disease Models, Animal; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007249:Inflammation; D007362:Intensive Care Units; D007700:Kinetics; D008070:Lipopolysaccharides / Q000737:chemistry; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000201:enzymology*; D012189:Retrospective Studies; D062606:Tertiary Care Centers; D013997:Time Factors
chemical_list: D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D010100:Oxygen