Airway remodeling in asthma is a process of structural changes occurring in the airway over time resulting in a component of fixed ainway obstruction. The clinical ramifications are significant, in that remodeling can lead to reduced lung function and reduced responsiveness to medications. The mechanisms whereby endogenous mediators of immune responses in asthma lead to the subsequent host response of airway remodesling are pooriy understood. We have shown that interleukin (IL)-13, a TH2 cytokine critical to the asthma phenotype, directs several critical and understudied remodeling processes in asthma including ainway fibroblast growth and matrix production. We have recently demonstrated that IL-13 also increases the production of hyaluronan (HA), a matrix glycosaminoglycan that is a normal constituent of basement membrane and makes up 10% of the proteoglycan content in the lung. HA can accumulate in the lung via activation of hyaluronan sythases (HAS) by mediators common in asthma, including tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-B). Low molecular weight (LMW) fragments (<500 kDa), but not the native form (>1000 kDa) of HA can signal via CD44, TLR2 and TLR4 to elicit inflammatory responses and further lung injury. IL-13 also directs ainway remodeling through the production and activation of two key groups of mediators, transforming growth factor-beta (TGF-B) and members of the matrix metalloproteinase (MMP) family. We present the exciting observation that IL-13 not only modulates matrix expression in the lung, but in combination with HA also plays a role in transforming the airway fibroblast to an invasive phenotype. We hypothesize that IL-13 is a critical regulator of remodeling that results in alteration in the airway matrix component hyaluronan that modulates the airway fibroblast to produce an invasive phenotype that contributes to remodeling and airway obstruction. To test this hypothesis, we will determine that in mouse and man, IL-13 augments HA producfion in asthma, is integral for the remodeling phenotype and elicits a robust infiammatory response in airway macrophages (aim 1).
In aim 2, we will demonstrate that IL-13, in combination with HA, produces an invasive fibroblast phenotype in asthma that is responsible for augmented matrix production and associated with a unique gene signature.
In aim 3, we will determine that infectious and non-infectious insults induce LMW HA production by the airway epithelial cell in asthma capable of signaling via TLR2 and TLR4. Thus, accumulafion of HA via IL-13,particulariy low molecular weight fragments, in the asthmatic airway due to tissue injury can elicit and perpetuate the inflammatory response.
This project is an integral part of the global goal of this program, which is how production of endogenous matrix components in the context of lung injury drives unremitting lung inflammation and flbrosis by interacting with cognate receptors leading to the development of an invasive pro-flbrotic flbroblast phenotype and perpetuation of remodeling. Project 3 will interface closely with Project 1 (Dr. Noble), as these concepts will be investigated in human and animal models of disease. Project 3 will also interface closely with Project 2 (Dr. Wright) to determine the role of innate immunity, particularly surfactant protein A, in this process.
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