Lung infections place a higher burden on public health than other major diseases such as HIV/AIDS, cancer coronary heart disease, and strokes (WHO data).^ The innate immune system, which is the body's first line of defense against lung infection, includes pathogen recognition receptors such as Toll-like receptors (TLRs), production of inflammatory mediators such as cytokines and chemokines, and leukocyte recruitment and activation. There is a paucity of information available with regard to the role of specific extracellular matrix (ECM) components in the innate immune response. Our preliminary data show that very little versican, an ECM proteoglycan, is present in healthy lungs but that the TLR4 agonist, lipopolysaccharide (LPS), as well as Pseudomonas aeruginosa and respiratory syncytial virus (RSV) rapidly increase versican accumulation in the extracellular space in the lungs of mice. This increase in versican occurs during the early phases of lung inflammation and coincides with leukocyte infiltration. Furthermore, our preliminary experiments show that human lung fibroblasts treated with the TLR3 agonist and viral mimetic, poly l:C produce a versican-enriched ECM that forms a macromolecular complex with another extracellular macromolecule, hyaluronan, to promote monocyte adhesion to the ECM in a versican-dependent manner. Our preliminary results and published work suggest that versican accumulation is important in the innate immune response to lung infection and have led us to formulate our Central Hypothesis, which is that versican plays a key role in the innate immune response to lung infection by promoting the adhesion, retention, and activation of monocytes, macrophages and neutrophils. We propose to determine the role of versican in the innate immune response to lung infection through completion of the following four Aims: (1) Define the composition and compartmentalization of the versican-enriched ECM that accumulates in the lungs of mice exposed to Pseudomonas aeruginosa and respiratory syncytial virus (RSV) Infection and determine its role in leukocyte adhesion;(2) Determine the TLRs and the TLR signaling pathways responsible for the accumulation of versican in the lungs of mice infected with P. aeruginosa and RSV;(3) Define the impact of versican on macrophage phenotype and function and determine the role of versican produced by pulmonary macrophages in the innate immune response to lung infection;and (4) Determine the requirement for versican in the innate immune response in the lungs of mice infected with P. aeruginosa and RSV.
In order to treat or prevent lung disease associated with bacterial or viral infection it is important to define key macromolecular components that are increased in the lung in response to infectious agents that influence the inflammatory response and that can be targeted for the treatment. We have identified one such component, versican, and we will perform a series of studies to establish the role of this molecule in infectious lung disease in order to develop strategies to prevent its pro-inflammatory activity.
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