The lung represents a major interface between the external world and our bodies. Thus, the lung must be able to effectively resist injurious agents while preventing an over-exuberant inflammatory response. When this does not occur, unregulated inflammation results in such common conditions as chronic obstructive pulmonary disease, asthma and the acute respiratory distress syndrome. In accordance with the mission of the NHLBI to improve the care of patients with lung disease, this proposal focuses on the role of two molecules, syndecan-1 and keratinocyte chemokine (KC), as modulators of this inflammatory response in the lung. Upon lung injury, the syndecan-1 :KC complex is shed from the cell surface through cleavage of the syndecan ectodomain by matrilysin, a matrix metalloprotelnase. The soluble complexes permit neutrophil activation. However, if the complex is not shed due to the absence of matrilysin, no activation is observed despite tissue injury. Remarkably, if the complex is completely absent, a similar lack of neutrophil activation is observed. This suggests that the syndecan-1 :KC complex serves as a checkpoint for lung Inflammation. The complex must first be present at the cell surface and then must be cleaved for proper neutrophil activation. The overall objective of this proposal is to Investigate the modulation of the inflammatory response by syndecan-1 and KG. Specifically, to test the role of ectodomain shedding syndecan-1 variants will be constructed that will be either resistant to shedding or constitutively shed. To examine the role of the syndecan-1 :KC complex, variants will be produced that lack the attachment sites for the glycosaminoglycan side chains important for this complex formation. These variants will be expressed in a bronchial epithelial cell line. Upon injury, the ability of these cells expressing the syndecan variants to activate or restrain neutrophils will be measured. The studies in this proposal will define important mechanisms in the proper regulation of inflammation. They will help to understand how the human body permits the immune system to activate in response to Injury but restricts it's activation in regions of intact tissue.
| Gill, Sean E; Nadler, Samuel T; Li, Qinglang et al. (2016) Shedding of Syndecan-1/CXCL1 Complexes by Matrix Metalloproteinase 7 Functions as an Epithelial Checkpoint of Neutrophil Activation. Am J Respir Cell Mol Biol 55:243-51 |
