title: Cathepsin G degradation of phospholipid transfer protein (PLTP) augments pulmonary inflammation.
abstract: Phospholipid transfer protein (PLTP) regulates phospholipid transport in the circulation and is highly expressed within the lung epithelium, where it is secreted into the alveolar space. Since PLTP expression is increased in chronic obstructive pulmonary disease (COPD), this study aimed to determine how PLTP affects lung signaling and inflammation. Despite its increased expression, PLTP activity decreased by 80% in COPD bronchoalveolar lavage fluid (BALF) due to serine protease cleavage, primarily by cathepsin G. Likewise, PLTP BALF activity levels decreased by 20 and 40% in smoke-exposed mice and in the media of smoke-treated small airway epithelial (SAE) cells, respectively. To assess how PLTP affected inflammatory responses in a lung injury model, PLTP siRNA or recombinant protein was administered to the lungs of mice prior to LPS challenge. Silencing PLTP at baseline caused a 68% increase in inflammatory cell infiltration, a 120 and 340% increase in ERK and NF-κB activation, and increased MMP-9, IL1β, and IFN-γ levels after LPS treatment by 39, 140, and 190%, respectively. Conversely, PLTP protein administration countered these effects in this model. Thus, these findings establish a novel anti-inflammatory function of PLTP in the lung and suggest that proteolytic cleavage of PLTP by cathepsin G may enhance the injurious inflammatory responses that occur in COPD.
authors.affiliation: 2Department of Medicine, St. Luke's Roosevelt, Mt. Sinai Health System, Antenucci Bldg., 432 West 58th St., Rm. 311, New York, NY 10019, USA. rforonjy@chpnet.org.
authors.forename: Anthony
authors.initials: A
authors.lastname: Brehm
authors.forename: Patrick
authors.initials: P
authors.lastname: Geraghty
authors.forename: Michael
authors.initials: M
authors.lastname: Campos
authors.forename: Itsaso
authors.initials: I
authors.lastname: Garcia-Arcos
authors.forename: Abdoulaye Jules
authors.initials: AJ
authors.lastname: Dabo
authors.forename: Adam
authors.initials: A
authors.lastname: Gaffney
authors.forename: Edward
authors.initials: E
authors.lastname: Eden
authors.forename: Xian-Cheng
authors.initials: XC
authors.lastname: Jiang
authors.forename: Jeanine
authors.initials: J
authors.lastname: D'Armiento
authors.forename: Robert
authors.initials: R
authors.lastname: Foronjy
mesh_terms: D000368:Aged; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D056649:Cathepsin G / Q000378:metabolism*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D049294:Phospholipid Transfer Proteins / Q000378:metabolism*; D011014:Pneumonia / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects
chemical_list: D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D049294:Phospholipid Transfer Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D007371:Interferon-gamma; D056649:Cathepsin G; D020780:Matrix Metalloproteinase 9
keywords: lipopolysaccharide; lung; protease; signaling