Smooth muscle proliferation is stimulated by the airway epithelium

Reynold A Panettieri

Short Communication - Journal of Pulmonology and Clinical Research (2021) Volume 4, Issue 6

Smooth muscle proliferation is stimulated by the airway epithelium

We hypothesized that an injured airway epithelium secretes soluble mediators at biologically relevant concentrations to stimulate smooth muscle cell hyperplasia. To address this hypothesis, we used a co-culture model of primary Normal Bronchial Epithelial Cells (NHBE) and primary normal Human Airway Smooth Muscle cells (HASM), as well as an in vivo model of epithelial injury in the rabbit trachea. Our results demonstrate that an injured airway epithelium promotes HASM cell proliferation. Furthermore, proliferation in the smooth muscle (trachealis) region was observed in the rabbit trachea after repeated epithelial injury. To our knowledge, this is the first report demonstrating the role of the epithelium in airway smooth muscle cell proliferation. The results are consistent with an increasing interest in epithelial dysfunction as a target of therapeutic intervention in airway diseases. Discussion Tissue injury along with inflammation is associated with remodeling as observed in several airway diseases including asthma, chronic obstructive pulmonary disease, and fibrosing alveolitis. One feature of airway remodeling is smooth muscle cell hyperplasia, which impacts airway caliber and decreases lung function. Current anti-inflammatory strategies do not reverse smooth muscle hyperplasia, creating a need for alternative therapies. Using both a novel in vitro co-culture model as well as an in vivo model of epithelial injury in the trachea, our study demonstrates that epithelial-derived mediators stimulate airway smooth muscle proliferation at baseline and after injury. We identified IL-6, IL-8, and MCP-1 as mediators, which contribute significantly to proliferation after injury, and MMP-9 as a novel mediator involved in both baseline and injury-induced proliferation. IL-6, IL-8, and MMP-9 levels are affected by the co-culture of NHBE and HASM, while MCP-1 is mainly produced by HASM. While not all diseases with epithelial injury manifest airway smooth muscle proliferation, our results provide potentially new targets to limit smooth muscle hyperplasia in the airways, and are consistent with a growing interest in the health of the airway epithelium.

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Abstract

Chronic tissue injury and inflammation triggered by exogenous stimuli can cause acute bronchoconstriction. Over time, structural changes such as goblet cell hyperplasia, subepithelial fibrosis, smooth muscle cell hypertrophy and hyperplasia, and increased vascularity and edema occur in the airway wall (airway remodeling). An intensive effort is aimed at understanding the mechanisms that lead to airway remodeling, in hopes of not only slowing, but perhaps reversing, the structural alterations. Airway epithelial cells play a critical role in the defense system of the lungs by providing an important barrier function to potentially toxic environmental agents that can promote epithelial damage, or induce bronchoconstriction in susceptible individuals. Not surprisingly, epithelial shedding, marked by increased numbers of epithelial cell clumps (creola bodies) in sputum and bronchial epithelium desquamation, are features of airway injury. The sequelae is an airway epithelium in a chronic state of wound repair, which secretes soluble mediators (e.g., IGF) necessary for cell proliferation, migration, and extracellular matrix synthesis consistent with a healing wound environment. Communication between the epithelium and the underlying fibroblast in the lamina propria is prevalent and normal during fetal lung development. In contrast, the airway smooth muscle lies adjacent to the lamina propria, and therefore a further distance from the epithelium. For the epithelium to influence smooth muscle cell behavior, soluble mediators would need to diffuse through the lamina propria. Hence, the vast majority of investigation has focused on the role of the epithelium in subepithelial fibrosis. Although progress has been made in identifying mitogenic stimuli of airway smooth muscle, the potential role of epithelium-derived mediators in smooth muscle proliferation remains unexplored.