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Published on: April 2, 2014
Midkine is expressed and differentially processed during chronic obstructive pulmonary disease exacerbations and
Helena M Linge1, Cecilia Andersson1, Sara L Nordin1
1Section for Respiratory Medicine and Allergology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
Abstract:
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.
Insights
Midkine (MK), an antimicrobial protein, is less effective against Staphylococcus aureus in chronic obstructive pulmonary disease (COPD) airways due to protease degradation. This impairs airway defense, particularly in COPD.
Area of Science:
- Pulmonary Medicine
- Infectious Diseases
- Immunology
Background:
- Staphylococcus aureus is a common pathogen in airway infections like ventilator-associated pneumonia (VAP) and chronic obstructive pulmonary disease (COPD) exacerbations.
- Antimicrobial proteins, such as midkine (MK), are crucial components of the airway's innate immune defense.
- Chronic inflammation in COPD may alter the airway environment and immune responses compared to acute inflammation in VAP.
Purpose of the Study:
- To investigate midkine (MK) levels and processing in relation to Staphylococcus aureus airway infections.
- To compare MK's role in chronic obstructive pulmonary disease (COPD) with preceding inflammation versus ventilator-associated pneumonia (VAP) with acute inflammation.
- To determine how bacterial and host proteases affect MK's antibacterial activity in different airway conditions.
Main Methods:
- Detection of MK in lung tissue and sputum from COPD and VAP patients.
- In vitro assessment of MK's bactericidal activity against Staphylococcus aureus.
- Analysis of MK degradation by bacterial proteases (aureolysin, staphopain A) and sputum proteases using zymography.
Main Results:
- Midkine (MK) was found in COPD lung tissue and sputum, and demonstrated in vitro bactericidal activity against Staphylococcus aureus.
- Bacterial proteases, specifically aureolysin, degraded MK, impairing its activity.
- MK degradation was more pronounced in sputum from COPD patients compared to VAP patients, indicating higher proteolytic activity in COPD.
Conclusions:
- Proteolytic degradation of midkine (MK) by both bacterial and host proteases compromises airway defense against Staphylococcus aureus.
- Chronic inflammation in COPD may exacerbate MK degradation, leading to impaired innate immunity.
- Understanding MK processing is vital for developing strategies to enhance airway defense in COPD and VAP.
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