Matrix metalloproteinases and matrix metalloproteinase inhibitors in acute lung injury

• Published in: Human pathology Vol. 37; no. 4; pp. 422 - 430
• Main Authors: Fligiel, Suzanne E.G., Standiford, Theodore, Fligiel, Helene M., Tashkin, Donald, Strieter, Robert M., Warner, Roscoe L., Johnson, Kent J., Varani, James
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-04-2006; Elsevier; Elsevier Limited
• Subjects: Acute lung injury; Acute respiratory distress syndrome; Biological and medical sciences; Bronchoalveolar lavage fluid; Bronchoalveolar Lavage Fluid - chemistry; Bronchoalveolar Lavage Fluid - cytology; Enzyme-Linked Immunosorbent Assay; Female; Humans; Investigative techniques, diagnostic techniques (general aspects); Lungs; Male; Matrix Metalloproteinase Inhibitors; Matrix metalloproteinases; Matrix Metalloproteinases - metabolism; Medical sciences; Middle Aged; Mortality; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Pneumology; Proteins; Pulmonary arteries; Respiratory distress syndrome; Respiratory Distress Syndrome, Adult - enzymology; Respiratory Distress Syndrome, Adult - mortality; Respiratory Distress Syndrome, Adult - pathology; Respiratory system : syndromes and miscellaneous diseases; Survival Rate; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Tissue Inhibitor of Metalloproteinase-2 - metabolism; Tissue inhibitor of metalloproteinases; Acute respiratory distress syndrome; Acute lung injury; Tissue inhibitor of metalloproteinases; Bronchoalveolar lavage fluid; Matrix metalloproteinases; Lung disease; Respiratory disease; Enzyme; Acute; Metalloendopeptidases; Tissue inhibitor metalloproteinase; Syndrome; Peptidases; Anatomic pathology; Bronchoalveolar lavage; Hydrolases; Respiratory distress; Inhibitor
• ISSN: 0046-8177; 1532-8392
• DOI: 10.1016/j.humpath.2005.11.023

The objective of this study was to assess matrix metalloproteinase (MMP) and MMP inhibitor expression in the airspace of patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) and to determine the prognostic significance of MMP expression in this patient population. Twenty-eight patients with ALI or ARDS were prospectively enrolled in this study; bronchoalveolar lavage (BAL) fluid obtained from these patients was examined for expression of MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin-1), MMP-8 (neutrophil collagenase), and MMP-9 (gelatinase B). Levels of MMP inhibitors (ie, tissue inhibitor of metalloproteinases-1 and -2 [TIMP-1 and TIMP-2]) were examined in parallel. Expression of MMPs was correlated with relevant clinical outcomes in patients with ALI/ARDS. In nearly all specimens obtained from patients with ALI/ARDS, there were high levels of MMP-2, MMP-8, MMP-9, and TIMP-1, but in only a small subset of patients (6/28) were there detectable levels of MMP-1 and/or MMP-3. In the patients with elevated MMP-1 and/or MMP-3, the mortality rate was higher (83%) than in the group without detectable levels of these enzymes (32%). Likewise, the overall severity of disease as indicated by Acute Physiology and Chronic Health Evaluation III scores was higher in this group (98 ± 30) than in the group without detectable MMP-1 or MMP-3 (78 ± 28). The percentage of individuals in whom lung disease was complicated by multiorgan failure was also higher in the group with detectable MMP-1 and/or MMP-3 (83%) than in the group without (64%), as was the number of organs that failed. In contrast, there was no correlation between MMP-1 and/or MMP-3 expression and impairment in gas exchange, as determined by the ratio of partial pressure of oxygen to fraction of inspired oxygen (Pa
o
2/F
io
2) on the day of BAL sample. Based on these findings, we conclude that elevated MMP-2, MMP-8, and MMP-9 in BAL fluid is a marker of acute lung injury (and, perhaps, a contributor to ALI) but is not necessarily an indicator of a poor outcome. On the other hand, the presence of detectable MMP-1 and/or MMP-3 is an indicator of more ominous disease progression.