Smooth Muscle Mechanisms in Dynamic Airway Properties

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Project Summary Airway smooth muscle (ASM) is a multifunctional tissue with complex physiologic properties. In addition to its well-known role in regulating airway narrowing, ASM produces and secretes immunomodulatory compounds, makes extracellular matrix (ECM) proteins, proliferates, and actively transitions between a contractile and a synthetic state in response to multiple cues from its local environment. In the lung, the extracellular environment of ASM cells may be modulated by both physiologic and pathophysiologic conditions that can alter airway tissue structure, ECM composition, and the mechanical forces imposed on the airways, all of which can trigger changes in the phenotype and physiologic responses of ASM to extracellular stimuli. The mechanisms by which the phenotypic and physiologic properties of ASM cells are modulated in response to extracellular conditions are critical for understanding the function of ASM under normal and pathophysiologic conditions. The adhesion junctions that connect cells to the ECM within tissues are composed of large multiprotein complexes termed adhesomes. Adhesomes play critical functions in cells that extend far beyond their structural role: while they provide mechanical coupling between cells and their matrix environment, they also enable cells to sense and respond to changes in the properties of their surrounding milieu. Our studies have shown that contractile and inflammatory stimuli trigger the assembly of membrane adhesome complexes in ASM tissues. These studies have led to a novel and detailed hypothesis for the molecular mechanisms for adhesome assembly in ASM in response to physiologic stimuli. We propose that this process is a fundamental process that is essential for the transduction of signals from diverse stimuli. However, the molecular mechanisms by which adhesome assembly is regulated to modulate signals to different downstream effector pathways are not understood. We hypothesize that S100A4, a member of the S100 protein family, and the α- and β-parvins, components of the trimeric integrin-linked kinase (ILK)-PINCH-parvin complex, are key intermediaries that play critical roles in adhesome assembly and in the differential activation of signaling pathways by extracellular stimuli in ASM. We also propose that S100A4 acts extracellularly on ASM tissues to promote inflammation and the synthetic phenotype. The proposed studies will employ ASM tissues and freshly dissociated differentiated ASM cells to address three Specific Aims: 1) Determine the role of S100A4 in regulating the response of ASM to contractile stimuli. 2) Determine the role of S100A4 as a mediator of inflammation and evaluate its role in airway inflammation using a murine model. 3) Determine the molecular mechanisms for the modulation of ASM phenotype in response to environmental and inflammatory stimuli. These studies will provide new insights into the molecular mechanisms of signal transduction in ASM that are likely to be broadly relevant to other cells and tissues, and that can provide new targets for therapeutic intervention in pathophysiologic conditions that result in airway hyperresponsiveness or inflammation.