Pulmonary fibrosis (PF) is an interstitial lung disease associated with high mortality. PF pathogenesis is a complex process where dysregulated inflammatory responses are thought to lead to the fibrotic phenotype. The molecular details of this dysregulated host response are not fully understood. Many potential mediators of PF pathogenesis have been identified during the last several decades. However, the mechanism as to how their activities are integrated and regulated during PF pathogenesis is poorly understood. Available data indicate that heparan sulfate proteoglycans (HSPGs) can regulate the activity of many key mediators of PF. Syndecan- 1 is the major cell surface HSPG of epithelia, including airway and alveolar epithelia. Activation of syndecan-1 shedding is one of the general host responses to tissue injury and inflammation, and shedding is activated in mice instilled with bleomycin, a potent inducer of lung inflammation and PF in humans and animals. Syndecan-1 is shed by metalloproteinases, such as matrix metalloproteinase (MMP)-7. The long-term objective of this research is to delineate how cell surface HSPGs regulate, in part, the highly complex mechanisms of PF pathogenesis. This proposal focuses on syndecan-1, and the goal is to define how syndecan-1 and its shedding function in lung inflammation and fibrosis. Four inter-related hypotheses will be tested in four Specific Aims: 1. Activation of syndecan-1 shedding by MMP-7 leads to the development of lung inflammation and fibrosis will be assessed by defining the molecular details of the syndecan-1-MMP-7 interactions; 2. Syndecan-1 ectodomains regulate lung inflammation and fibrosis by modulating chemokines will be evaluated by determining how syndecan-1 binds to the CXC chemokine KC and affects it's functions; 3. PF will be attenuated in the absence of syndecan-1, but exacerbated in the excess of syndecan-1 will be probed by determining how syndecan-1 null and overexpressing mice respond to bleomycin; and 4. Syndecan-1 shedding is activated in human PF will be assessed by measuring levels of shed syndecan-1 in bronchoalveolar lavage fluids and serum of patients with PF and other lung diseases. These studies, which will delineate how cell surface HSPGs such as syndecan-1 function during the pathogenesis of lung inflammation and fibrosis, should provide a foundation for the development of novel therapeutic agents and screening methods to combat PF and other lung diseases.
