Serum Response Factor Overexpression, a Double Trouble that May Underlie Airway Hyperresponsiveness in Asthma

Airway hyperresponsiveness in asthma is associated with airway remodeling characterized by the increase in the mass of all layers of an airway, including airway adventitia, submucosa, and smooth muscle (1). It has been argued, on the basis of mathematical modeling, that the increase in airway smooth muscle (ASM) mass is likely the most significant contributor to the increase in airway resistance in a bronchochallenged lung (2). A counterargument, which is based on our conventional understanding of ASM phenotype change (3) is that the hypertrophic and hyperplastic muscle cells may contain less contractile proteins and, thus, be less contractile. In this case, ASM may not be as culpable for airway hyperresponsiveness as that predicted from the observed increase in asthmatic ASM mass. A more recent study (4), however, showed that in human asthmatic lungs, intrapulmonary ASM is hyperreactive, suggesting that airway remodeling associated with asthma does not reduce ASM contractility. To the contrary, it appears that airway remodeling may come with a double whammy: ASM hypercontractility (from cell hypertrophy and hyperplasia) and hypersecretion of inflammatory mediators. Both can contribute to airway hyperresponsiveness. As the lyrics from the theme song of Harry Potter and the Prisoner of Azkaban go, “Double, double, toil and trouble, something wicked this way comes!” the wickedness of the double trouble presents an enormous challenge for researchers seeking a solution to alleviate airway hyperresponsiveness in asthma.

How could asthmatic ASM get itself into such a bind? In this issue of the Journal, through a series of carefully designed and executed experiments, Sun and colleagues (pp. 182–194) provide important and interesting insights into the molecular mechanisms underlying this wicked problem (5). Phenotype change in ASM is controlled by the interactions of myocardin (MyoCD) and ETS-like-1 protein (Elk-1) with serum response factor (SRF). More specifically, binding of MyoCD with SRF leads to myogenic gene expression, promoting a contractile phenotype, whereas Elk-1 binding with SRF leads to mitogenic gene expression and a commensurate proliferative and secretory phenotype. Furthermore, the binding of MyoCD and Elk-1 with SRF appears to be competitive and mutually inhibitory, leading to a transformation in ASM phenotype toward either contractile or proliferative (6). The discovery by Sun and colleagues here adds a layer of complexity to the relatively simple model of dichotomy in ASM phenotype. They found that overexpression of SRF allows MyoCD and Elk-1 to induce myogenic and mitogenic gene expressions simultaneously, leading to the double trouble of ASM being hypercontractile and hyperproliferative/hypersecretory at the same time. This abnormal and wicked state of ASM has the potential to alter lung function and make the lung hyperresponsive. The maladaptation of ASM can also be a broader part of the asthma pathology.

The RhoA-ROCK (a.k.a. Rho-kinase) signaling pathway promotes upregulation of SRF and its nuclear translocation (3). Sun and colleagues demonstrate the effect of ROCK inhibition to limit SRF upregulation and nuclear translocation mediated by FBS, thus reversing the dual contractile-proliferative phenotype. The findings reveal a potential strategy in treating airway hyperresponsiveness by limiting SRF upregulation through inhibition of ROCK. Overexpression of ROCK is found in human asthmatic ASM (7). Abnormally enhanced ROCK signaling can, in many ways, adversely modify ASM behavior and make the lung unresponsive to the bronchodilatory and bronchoprotective effects of deep inspirations (8), resembling that of an asthmatic lung (9, 10). Inhibition of ROCK is, therefore, a plausible approach in restoring the beneficial effects of deep inspiration in asthmatic lungs. Findings from Sun and colleagues provide another reason for keeping the RhoA-ROCK signaling in check in the ASM of asthmatic patients and that is to limit upregulation of nuclear SRF.

The study by Sun and colleagues provides a mechanistic explanation for the existence of a dual state in a diseased ASM where contractile and proliferative phenotypes can be present simultaneously. This understanding also suggests strategies for mitigation. One caveat is that the insights from the study derive exclusively from experiments using cultured cells. Assessment of ASM contractility was also limited to using a gel contraction model and elicited by high [K⁺] depolarization. For the findings to be more physiologically relevant and more pertinent to our understanding of the pathophysiology associated with asthmatic lungs, and for development of effective treatments for asthma, they need to be confirmed at the tissue and organ levels and, ultimately, verified in human patients with asthma. One important question that needs to be addressed is: What kind of disease state can promote SRF overexpression? Also, besides ROCK inhibition, what interventions can be made to prevent SRF overexpression? That being said, the observations made by Sun and colleagues are novel and highly significant in aiding our quest to find new drug targets for the treatment of asthma.