Asthma can manifest with varying levels of severity. Whereas the acute phase of mild and moderate asthma is characterized largely by rapid infiltration of a number of immune cell types within the lungs, such as T lymphocytes, eosinophils, and mast cells, severe asthma has additional inflammatory and remodeling features that are thought to strongly contribute to decline in lung function. These include smooth muscle changes (hypertrophy, hyperplasia and contractile hyperresponsiveness), and subepithelial fibrosis. Fibrosis is due to deposition of extracellular matrix proteins such as collagen, fibronectin, fibrillin, and laminin, thought to be produced largely by differentiating fibroblasts, but which might also be products of smooth muscle cells. Fibroblasts can additionally be induced to express α-smooth muscle actin and other contractile proteins and may further contribute to increased rigidity of the airways together with the mature smooth muscle cells that line the bronchioles. The changes in activity of lung fibroblasts and smooth muscle cells linked to severe asthma are not fully understood, but are thought to be driven by factors derived from immune cells, of which IL-13 and IL-17 have been proposed to be key contributors. However, the true diversity and range of activities of fibroblasts and smooth muscle cells in severe asthmatics is not known nor how they differ from those in the lungs of mild asthmatics. Recent data are finding that multiple phenotypes of structural cells are seen in the tissues of patients with chronic immune diseases, such as ulcerative colitis, rheumatoid arthritis, systemic sclerosis, and atopic dermatitis, suggesting that cooperative and synergistic effects of several inflammatory factors might lead to these alternate pathogenic phenotypes that are important for severe disease. In this regard, we have found, in animal models of severe asthma, that two members of the tumor necrosis factor (TNF) superfamily, LIGHT (TNFSF14) interacting with its two receptors HVEM (TNFRSF14) and LTβR (TNFRSF3), and TL1A (TNFSF15) interacting with its receptor DR3 (TNFRSF25), are central mediators and drivers of the fibrotic and remodeling activity in the lungs resulting from chronic exposure to allergen. Furthermore, the receptors for LIGHT and TL1A are expressed on human lung fibroblasts and human airway smooth muscle cells, and both cytokines have strong activity in modulating inflammatory or contractile proteins in these cells. This proposal will pursue the hypothesis that both LIGHT and TL1A are new mediators of human airway remodeling in severe asthma and that these factors cooperate together, and with IL-13 and IL-17, to drive distinct pathogenic phenotypes in lung fibroblasts and smooth muscle cells that are associated with severe asthma. The treatment options for asthmatics are currently limited. Understanding the functional response that is elicited from the signals delivered by LIGHT and TL1A to hum...