Matrix metalloproteinases and matrix metalloproteinase inhibitors in acute lung injury

Summary

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 (Pao₂/Fio₂) 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.

Introduction

The matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that collectively have the capacity to degrade virtually every component of the extracellular matrix [1]. Chronic inflammatory lung diseases, including airway-specific diseases such as asthma, cystic fibrosis (CF), and non-CF bronchiectasis, as well as parenchymal lung diseases including emphysema, idiopathic pulmonary fibrosis, and silicosis/asbestosis have in common the increased expression of one or more MMPs [2], [3], [4], [5], [6]. Matrix metalloproteinase expression in acute lung inflammation has also been studied, but to date, virtually all of the data relate to neutrophil-derived enzymes. For example, Ricou et al [7] found that MMP-9 (92-kd gelatinase B) was increased in bronchoalveolar lavage (BAL) fluid of patients with acute respiratory distress syndrome (ARDS) secondary to severe trauma or septic shock in comparison with normal controls. Two studies identified elevated MMP-2 and MMP-9 levels in the lungs of newborns with acute respiratory distress [8], [9]. Patients with pneumonia [10], [11], [12] have also been shown to exhibit increased MMP-9 expression. In many, but not all of these patients, MMP-2 (72-kd gelatinase A) levels were also increased. Although these studies demonstrate that elevated MMP-2 and MMP-9 levels distinguish individuals with acute lung disease from normal controls, it is not clear if differences in the levels of these MMPs among patients with acute inflammatory lung disease have pathophysiological or prognostic significance.

In addition to MMP-9 and MMP-2, several other MMPs are elaborated by inflammatory cells and could play pathogenic roles in acute lung disease. To date, however, this has not been addressed in detail. MMP-8 (neutrophil collagenase) has been identified in BAL fluid of acutely ill adult and neonatal patients [8], [9], [12]. In these studies, elevated MMP-8 was associated with the presence of large numbers of neutrophils in lung tissue. In one of the studies [8], MMP-1 (interstitial collagenase) was also assessed. Measurable levels of this enzyme were not detected in any of the specimens examined. Given this background, the present study was undertaken to assess the expression of several physiologically relevant MMPs including MMP-1, MMP-3 (stromelysin-1), and MMP-8, as well as MMP-2 and MMP-9, in BAL fluid from patients with acute lung injury (ALI/ARDS). Levels of MMP inhibitors (ie, tissue inhibitor of metalloproteinases-1 and -2 [TIMP-1 and TIMP-2]) were examined in parallel. Our data show that MMP-2, MMP-8, and MMP-9 were strongly up-regulated in BAL fluid from nearly all patients with ALI or ARDS, whereas MMP-1 and MMP-3 were detectable in only a small subset of individuals. Of interest, however, in the subset of patients in whom MMP-1 and/or MMP-3 was detected, the severity of illness and overall mortality rate were higher than in the group in which only MMP-2, MMP-8, and MMP-9 were detected.