Infection and inflammation are common complications of chronic lung diseases and result in clinical exacerbations. The long term objective of this proposal is to identify means to control inflammation and infection in chronic airways disease. Recent evidence indicates that lung epithelial cells respond to the bacterial cell wall component, lipopolysaccharide (LPS), through interaction with TLR4 in conjunction with sCD14, MD2 and LPS binding protein. The cellular inflammatory response to LPS may be further modulated by Bactercidal/Permeability Increasing Protein (BPI). BPI, a well known product of neutrophils, functions to kill bacteria and neutralize LPS. We recently discovered that both human and murine lung epithelial cells express BPI. Currently, nothing is known about the role of lung epithelial cell BPI in LPS signaling. The goal of this proposal is to determine the role of BPI in LPS signaling in epithelial cells and its effect on LPS induced airway inflammation. We plan to characterize functional activity and cellular expression of BPI in human and murine epithelial cells in vitro. In future studies we will extend this basic information about the mechanisms by which BPI modulated LPS signaling to a murine model of bacterial pneumonia and LPS-induced lung inflammation. These studies are expected to provide the foundation for therapeutic strategies that augment or supplement BPI in the airways of patients with infection and inflammation. Early treatment might offer the prospect of minimizing early infection and antibiotic resistance.
. Bactercidal/Permeability Increasing Protein (BPI), expressed in granules and on the surface of neutrophils, is a member of the CLTP family and functions to neutralize LPS. This proposal was motivated by our recent discovery that genetic variation in the BPI gene significantly increases the risk for development of obstructive lung disease after hematopoietic stem cell transplant. Further, we made the novel observation that BPI is expressed by lung epithelial cells. Currently, nothing is known about the role of lung epithelial cell BPI in LPS signaling. However, recurrent airway infection and LPS expression are common in chronic airway disease such as asthma, cystic fibrosis, and chronic bronchiolitis. Delineation of BPI as a molecular modifier of airway infections and inflammation could form the basis for future therapeutic interventions during infections and exacerbations of chronic lung disease. The goal of this proposal is to determine the role of epithelial BPI in LPS signaling in epithelial cells and its effect on airway infection and LPS induced airway inflammation.
| Clark, Joan G; Kim, Kyoung-Hee; Basom, Ryan S et al. (2015) Plasticity of airway epithelial cell transcriptome in response to flagellin. PLoS One 10:e0115486 |
