Midkine Is Expressed and Differentially Processed during Chronic Obstructive Pulmonary Disease Exacerbations and Ventilator-Associated Pneumonia Associated with Staphylococcus aureus Infection
Staphylococcus aureus is sometimes isolated from the airways during acute exacerbations of chronic obstructive pulmonary disease (COPD) but more commonly recognized as a cause of ventilator-associated pneumonia (VAP). Antimicrobial proteins, among them midkine (MK), are an important part of innate immunity in the airways. In this study, the levels and possible processing of MK in relation to S. aureus infection of the airways were investigated, comparing COPD and VAP, thus comparing a state of disease with preceding chronic inflammation and remodeling (COPD) with acute inflammation (that is, VAP). MK was detected in the small airways and alveoli of COPD lung tissue but less so in normal lung tissue. MK at below micromolar concentrations killed S. aureus in vitro. Proteolytic processing of MK by the staphylococcal metalloprotease aureolysin (AL), but not cysteine protease staphopain A (SA), resulted in impaired bactericidal activity. Degradation was seen foremost in the COOH-terminal portion of the molecule that harbors high bactericidal activity. In addition, MK was detected in sputum from patients suffering from VAP caused by S. aureus but less so in sputum from COPD exacerbations associated with the same bacterium. Recombinant MK was degraded more rapidly in sputum from the COPD patients than from the VAP patients and a greater proteolytic activity in COPD sputum was confirmed by zymography. Taken together, proteases of both bacteria and the host contribute to degradation of the antibacterial protein MK, resulting in an impaired defense of the airways, in particular, in COPD where the state of chronic inflammation could be of importance.
We thank Pia Andersson and Maria Baumgarten for excellent technical assistance and Staffan Arvidson for providing the S. aureus strains 8325-4 and sarA.
This work was supported by the Swedish Research Council (projects A0615601 HML and 2010-4224AE); the Swedish Heart and Lung Foundation (20100164); the Medical Faculty of Lund University; Swedish Government Funds for Clinical Research (ALF); and the foundations of Bergh, Greta and Johan Kock, and Alfred Österlund.
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