# Project-002

> **NIH NIH U19** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $445,000

## Abstract

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...

## Key facts

- **NIH application ID:** 10869418
- **Project number:** 5U19AI070535-18
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** DAVID H BROIDE
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $445,000
- **Award type:** 5
- **Project period:** 2006-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10869418

## Citation

> US National Institutes of Health, RePORTER application 10869418, Project-002 (5U19AI070535-18). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10869418. Licensed CC0.

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