Journal
FASEB JOURNAL
Volume 28, Issue 5, Pages 2318-2331Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.13-246843
Keywords
lung; lipopolysaccharide; protease; signaling
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Funding
- Flight Attendant Medical Research Institute [YCSA 24039, CIA 074047, YCSA 113380]
- U.S. National Institutes of Health (NIH) [5R01HL-098528-04]
- NIH [R01HL-086936]
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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-B activation, and increased MMP-9, IL1, and IFN- 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.Brehm, A., Geraghty, P., Campos, M., Garcia-Arcos, I., Dabo, A. J., Gaffney, A., Eden, E., Jiang, X.-C., D'Armiento, J., Foronjy, R. Cathepsin G degradation of phospholipid transfer protein (PLTP) augments pulmonary inflammation.
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