Excessive accumulation of smooth muscle in the airway (smooth muscle remodeling), may contribute to airway obstruction and disease progression in asthma, and recent studies have identified factors that could contribute to this process. At the same time, basic immunological research suggests that asthma is fundamentally a T helper type 2 (Th2)-driven inflammatory disease. However, whether Th2 inflammation is the major factor underlying airway remodeling in human asthma is uncertain. Our preliminary data demonstrate that the canonical mediator of Th2 inflammation in the airway, interleukin-13 (IL-13), drives inflammation in only a subset of patients with asthma. This subset with "IL-13-driven" asthma comprises half of our asthmatics and represents a distinct clinical and pathological phenotype. With regard to smooth muscle, our preliminary data indicate that remodeling is markedly increased in "IL-13 driven" asthma, suggesting that Th2 inflammation contributes directly to smooth muscle remodeling in human asthma. Our data also identify a matricellular protein, periostin, as a mediator which may link IL-13 driven inflammation to airway remodeling in asthma. On the other hand, our data suggest that some degree of smooth muscle remodeling may be present in "non-IL-13 driven" asthma as well, implying additional non-Th2-driven pathways in some patients. If so, this implies that ASM remodeling is a fundamental abnormality common to all phenotypes of asthma. On the basis of these data, we propose three aims to address the following hypotheses: 1) that IL-13-driven inflammation enhances ASM remodeling, 2) that periostin, secreted by resident lung cells in response to IL-13, mediates ASM remodeling in "IL-13 driven" asthma, and 3) that additional non-IL-13 driven pathways contribute to ASM remodeling in some patients and that these pathways can be identified using translational and genomic approaches. These studies will be performed in vivo by applying bronchoscopy, design-based stereology, laser capture microdissection and genomics in a detailed study of asthmatics and healthy controls and in vitro using cell culture models. These studies will leverage innovative methodologies for the study of ASM in humans and address the interplay between inflammation, remodeling and ASM synthetic function. Importantly, our results will address a critical barrier to progress in the field, whatever the result. If ASM remodeling is enhanced in "IL- 13 driven asthma", then strategies that target Th2 inflammation or specific downstream mediators such as periostin, should improve ASM remodeling. However, if ASM remodeling can also occur in "non-IL-13-driven" asthma, then our studies will guide further research in the field by directing attention to non-Th2 pathways of ASM dysfunction in asthma which may be novel and are not targeted by current therapies.

Public Health Relevance

Excessive accumulation of smooth muscle in the airway (smooth muscle remodeling) is thought to contribute to disease progression in asthma, however, whether this remodeling is caused by T-helper type 2 driven (allergic) inflammation or by non T-helper type 2 driven mechanisms is uncertain. This grant will determine the contribution of T-helper type 2 driven inflammation to smooth muscle remodeling and investigate the roles of novel mediators in ASM remodeling including a matricellular protein, periostin, and additional non T-helper type 2 related mediators of remodeling.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL097591-04
Application #
8322625
Study Section
Special Emphasis Panel (ZHL1-CSR-A (M1))
Program Officer
Banks-Schlegel, Susan P
Project Start
2009-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$427,315
Indirect Cost
$150,736
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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