Pulmonary Matrix Metalloproteinase Excess in Hospital-acquired Pneumonia

Abstract

In hospital-acquired pneumonia, extracellular matrix destruction is common and may be caused by excessive activity of matrix metalloproteinases (MMPs). Thirty patients with hospital-acquired pneumonia and 16 control subjects were studied. We evaluated the concentrations of MMP-8, MMP-9, and tissue inhibitor of metalloproteinase-1 in mini-bronchoalveolar lavage fluid (mini-BALF) and blood using zymography and specific immunoassays. In patients with hospital-acquired pneumonia concentrations of MMP-8 and MMP-9 in mini-BALF were increased 10-fold, whereas their specific inhibitor tissue inhibitor of metalloproteinase-1 was not concomitantly increased. In 80% of patients with pneumonia, but in none of the control subjects, the active form of MMP-9 was detected by zymography. Zymography furthermore showed the banding pattern of neutrophil-derived MMP-9, indicating that neutrophils were the main source of MMP-9. Comparison of neutrophils from blood and mini-BALF showed higher basal release of MMPs by pulmonary neutrophils. Stimulation analysis indicated that pulmonary neutrophils were already maximally activated. In patients with detection of potentially pathogenic microorganisms, concentrations of MMPs were fivefold increased compared with patients with negative cultures. Furthermore, MMP-levels were related to clinical severity. These are the first data suggesting that neutrophil-derived MMPs are increased in hospital-acquired pneumonia in association to the detection of causative microorganisms and clinical severity.

Elevated serum matrix metalloproteinase-2 and -9 and their correlationswith severity of disease in patients with community-acquired pneumonia

“…We performed a zymographic analysis to determine active and inactive MMPs in the serums of CAP patients and controls. Active forms of MMP-2 and MMP-9 were 13 and 17 times higher, respectively, in CAP patients than controls, making our findings consistent with the results of previous studies (6,23,24,(26)(27)(28).…”

“…Furthermore, patients with severe pneumonia have higher MMP-2 levels and lower α-2 macroglobulin levels than nonsevere CAP patients, but the MMP-9 serum levels are the same. On the other hand, Hartog et al (24) reported higher MMP-8 and MMP-9 levels both in serum and mini-BAL fluid in HAP patients with a clinical pulmonary infection score (CPIS) of ≥7 than in patients with CPIS of <7, but no difference in TIMP-1 levels. The CPIS was originally proposed by Pugin et al (35,36) based on six variables (fever, leukocytosis, oxygenation, radiographic infiltrates, and tracheal aspirates and semiquantitative cultures of tracheal aspirates with Gram stain).…”

“…Previous studies found that leukocytes/neutrophils can release a variety of extracellular matrix-degrading proteases, with a significant positive correlation between MMP-9 concentration and activity in mini-BAL fluid or serum (6,24). In contrast to these findings, however, we found no significant correlation between MMPs and leukocytes in the serum, although we did obtain similar results to those of Chiang et al (27), namely that MMP-9 and TIMP-1 serum levels and CRP, leukocyte, and neutrophil counts decreased following successful antibiotic treatment.…”

“…Higher levels and activities of MMP-8 and -9 have been detected in patients with hospital-acquired and ventilator-associated pneumonia (22)(23)(24). Recently, increased MMP-9 activity and MMP-9 levels in the plasma of CAP patients were observed in three studies from the same institution (6,26,27).…”

Bronchoalveolar Lavage MMP-9 and TIMP-1 in Preschool Wheezers and Their Relationship to Persistent Wheeze

“…Bacteria are frequently isolated from BAL in preschool wheezers and their presence is cited as being from upper respiratory tract contamination of the bronchoscope (33-37). TIMP-1 was reduced in these children, like adults with pneumonia (38), suggesting that bacteria are proinflammatory; however, other markers of inflammation like IL-8 were not increased in this group. If high TIMP-1 is associated with persistent wheezing, then the lower TIMP-1 concentrations in children with positive bacterial cultures may be a marker of protection in keeping with the hygiene hypothesis, where bacterial infection reduces the subsequent risk of allergic disease.…”