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Ventilator-Associated Pneumonia Is Characterized by Excessive Release of Neutrophil Proteases in the Lung

Lookup NU author(s): Professor John SimpsonORCiD


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Background: Ventilator-associated pneumonia (VAP) is characterized by neutrophils infiltrating the alveolar space. VAP is associated with high mortality, and accurate diagnosis remains difficult. We hypothesized that proteolytic enzymes from neutrophils would be significantly increased and locally produced inhibitors of human neutrophil elastase (HNE) would be decreased in BAL fluid (BALE) from patients with confirmed VAP. We postulated that in suspected VAP, neutrophil proteases in BALE may help identify "true" VAP. Methods: BAL was performed in 55 patients with suspected VAP and in 18 control subjects. Isolation of a pathogen(s) at > 104 colony-forming units/mL of BALE dichotomized patients into VAP (n = 12) and non-VAP (n = 43) groups. Matrix metalloproteinases (MMPs), HNE, inhibitors of HNE, and tissue inhibitors of matrix metalloproteinases (TIMPs) were quantified. Plasminogen activator (PA) activity was estimated by sodium dodecyl sulfate polyacrylamide gel electrophoresis and zymography. Results: Neutrophil-derived proteases HNE, MMP-8, and MMP-9 were significantly increased in cell-free BALE from patients with VAP as compared with those without VAP (median values: HNE, 2,708 ng/mL vs 294 ng/mL,P < .01; MMP-8, 184 ng/mL vs 5 ng/mL, P < .01; MMP-9, 310 ng/mL vs 11 ng/mL, P < .01). HNE activity was also significantly increased in VAP (0.45 vs 0.01 arbitrary units; P < .05). In contrast, no significant differences were observed for protease inhibitors, TIMPs, or PAs. HNE in BALE, at a cutoff of 670 ng/mL, identified VAP with a sensitivity of 93% and specificity of 79%. Conclusions: Neutrophil proteases are significantly elevated in the alveolar space in VAP and may contribute to pathogenesis. Neutrophil proteases appear to have potential in suspected VAP for distinguishing true cases from "non-VAP" cases. CHEST 2012; 142(6):1425-1432

Publication metadata

Author(s): Wilkinson TS, Morris AC, Kefala K, O'Kane CM, Moore NR, Booth NA, McAuley DE, Dhaliwal K, Walsh TS, Haslett C, Sallenave JM, Simpson AJ

Publication type: Article

Publication status: Published

Journal: Chest

Year: 2012

Volume: 142

Issue: 6

Pages: 1425-1432

Print publication date: 01/12/2012

ISSN (print): 0012-3692

ISSN (electronic): 1931-3543

Publisher: American College of Chest Physicians


DOI: 10.1378/chest.11-3273


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