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

Thomas S Wilkinson, Andrew Conway-Morris, Kallirroi Kefala, Cecilia M O'Kane, Norma R Moore, Nuala A Booth, Daniel F McAuley, Kevin Dhaliwal, Timothy S Walsh, Christopher Haslett, Jean-Michel Sallenave, A John Simpson

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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) decreased - in bronchoalveolar lavage fluid (BALF) from patients with confirmed VAP. We postulated that in suspected VAP, neutrophil proteases in BALF may help identify 'true' VAP.

Methods: BAL was performed in 55 patients with suspected VAP and in 18 age- and sex-matched volunteers. Isolation of a pathogen(s) at >104 colony forming units per ml of BALF 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 SDS-PAGE and zymography.

Results: Neutrophil-derived proteases HNE, MMP-8 and MMP-9 were significantly increased in cell-free BALF from patients with VAP as compared with non-VAP (median values: HNE, 2708 versus 294 ng/ml, p<0.01; MMP-8 184 versus 5 ng/ml, p<0.01; MMP-9 310 versus 11 ng/ml, p<0.01). HNE activity was also significantly increased in VAP (0.45 versus 0.01 arbitrary units, p<0.05). In contrast, no significant differences were observed for protease inhibitors, TIMPs or PAs. HNE in BALF, at a cut off 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.
Original languageEnglish
Pages (from-to)1425-1432
Number of pages8
JournalChest Journal
Issue number6
Publication statusPublished - Dec 2012


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