title: Osteopontin That Is Elevated in the Airways during COPD Impairs the Antibacterial Activity of Common Innate Antibiotics.
abstract: Bacterial infections of the respiratory tract contribute to exacerbations and disease progression in chronic obstructive pulmonary disease (COPD). There is also an increased risk of invasive pneumococcal disease in COPD. The underlying mechanisms are not fully understood but include impaired mucociliary clearance and structural remodeling of the airways. In addition, antimicrobial proteins that are constitutively expressed or induced during inflammatory conditions are an important part of the airway innate host defense. In the present study, we show that osteopontin (OPN), a multifunctional glycoprotein that is highly upregulated in the airways of COPD patients co-localizes with several antimicrobial proteins expressed in the airways. In vitro, OPN bound lactoferrin, secretory leukocyte peptidase inhibitor (SLPI), midkine, human beta defensin-3 (hBD-3), and thymic stromal lymphopoietin (TSLP) but showed low or no affinity for lysozyme and LL-37. Binding of OPN impaired the antibacterial activity against the important bacterial pathogens Streptococcus pneumoniae and Pseudomonas aeruginosa. Interestingly, OPN reduced lysozyme-induced killing of S. pneumoniae, a finding that could be explained by binding of OPN to the bacterial surface, thereby shielding the bacteria. A fragment of OPN generated by elastase of P. aeruginosa retained some inhibitory effect. Some antimicrobial proteins have additional functions. However, the muramidase-activity of lysozyme and the protease inhibitory function of SLPI were not affected by OPN. Taken together, OPN can contribute to the impairment of innate host defense by interfering with the function of antimicrobial proteins, thus increasing the vulnerability to acquire infections during COPD.
authors.affiliation: Respiratory Medicine & Allergology, Department of Clinical Sciences Lund, Lund University, SE-221 84, Lund, Sweden.
authors.forename: Anele
authors.initials: A
authors.lastname: Gela
authors.affiliation: Respiratory Medicine & Allergology, Department of Clinical Sciences Lund, Lund University, SE-221 84, Lund, Sweden.
authors.forename: Ravi K V
authors.initials: RK
authors.lastname: Bhongir
authors.affiliation: Airway Inflammation Unit, Department of Experimental Medical Sciences, Lund University, SE-221 84, Lund, Sweden.
authors.forename: Michiko
authors.initials: M
authors.lastname: Mori
authors.affiliation: Respiratory Medicine & Allergology, Department of Clinical Sciences Lund, Lund University, SE-221 84, Lund, Sweden.
authors.forename: Paul
authors.initials: P
authors.lastname: Keenan
authors.affiliation: Infection Medicine, Department of Clinical Sciences Lund, Lund University, SE-221 84, Lund, Sweden.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.affiliation: Airway Inflammation Unit, Department of Experimental Medical Sciences, Lund University, SE-221 84, Lund, Sweden.
authors.forename: Jonas S
authors.initials: JS
authors.lastname: Erjefält
authors.affiliation: Infection Medicine, Department of Clinical Sciences Lund, Lund University, SE-221 84, Lund, Sweden.
authors.forename: Heiko
authors.initials: H
authors.lastname: Herwald
authors.affiliation: Respiratory Medicine & Allergology, Department of Clinical Sciences Lund, Lund University, SE-221 84, Lund, Sweden.
authors.forename: Arne
authors.initials: A
authors.lastname: Egesten
authors.affiliation: Respiratory Medicine & Allergology, Department of Clinical Sciences Lund, Lund University, SE-221 84, Lund, Sweden.
authors.forename: Gopinath
authors.initials: G
authors.lastname: Kasetty
mesh_terms: D001424:Bacterial Infections / Q000150:complications / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007781:Lactoferrin / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D000078792:Midkine; D053495:Osteopontin / Q000378:metabolism*; D011485:Protein Binding; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000378:metabolism* / Q000382:microbiology; D012141:Respiratory Tract Infections / Q000150:complications / Q000378:metabolism* / Q000382:microbiology; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000302:isolation & purification; D017211:Treatment Failure; D015854:Up-Regulation; D023083:beta-Defensins / Q000378:metabolism; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; C422950:DEFB103A protein, human; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; D023083:beta-Defensins; D053495:Osteopontin; D000078792:Midkine; D007781:Lactoferrin; D000094632:Thymic Stromal Lymphopoietin