Pathobiology of Airway Remodeling in Asthma: The Emerging Role of Integrins

Abstract

Airway remodeling is a complex clinical feature of asthma that involves long-term disruption and modification of airway architecture, which contributes significantly to airway hyperresponsiveness (AHR) and lung function decline. It is characterized by thickening of the airway smooth muscle layer, deposition of a matrix below the airway epithelium, resulting in subepithelial fibrosis, changes within the airway epithelium, leading to disruption of the barrier, and excessive mucous production and angiogenesis within the airway wall. Airway remodeling contributes to stiffer and less compliant airways in asthma and leads to persistent, irreversible airflow obstruction. Current asthma treatments aim to reduce airway inflammation and exacerbations but none are targeted towards airway remodeling. Inhibiting the development of airway remodeling or reversing established remodeling has the potential to dramatically improve symptoms and disease burden in asthmatic patients. Integrins are a family of transmembrane heterodimeric proteins that serve as the primary receptors for extracellular matrix (ECM) components, mediating cell-cell and cell-ECM interactions to initiate intracellular signaling cascades. Cells present within the lungs, including structural and inflammatory cells, express a wide and varying range of integrin heterodimer combinations and permutations. Integrins are emerging as an important regulator of inflammation, repair, remodeling, and fibrosis in the lung, particularly in chronic lung diseases such as asthma. Here, we provide a comprehensive summary of the current state of knowledge on integrins in the asthmatic airway and how these integrins promote the remodeling process, and emphasize their potential involvement in airway disease.

Keywords: airway remodeling; asthma; biomechanics; fibrosis; integrins; matrix.

Figure 1

Schematic diagram giving an overview of how different integrin heterodimers expressed by a variety of lung cell types may contribute to the development and/or progression of airway remodeling in asthma. Both environmental and cellular stimuli converge upon integrin signaling pathways in a variety of cell types to contribute to airway hyper-responsiveness and ASM thickening, mucous over-production, subepithelial fibrosis, new blood vessel formation, and airway inflammation.