Reduced allergic lung inflammation and airway responsiveness in mice lacking the cytoskeletal protein gelsolin

Asthma is a chronic inflammatory disease of the airways that causes symptoms including shortness of breath, chest tightness, coughing and wheezing. Asthma includes inflammation and narrowing of the bronchial tubes, which leads to limited airflow and difficulty breathing. Continuous inflammation regulated by immune responses causes chronic structural changes in the airway including smooth muscle hypertrophy and hyperplasia. Gelsolin, an actin-depolymerizing protein expressed both in extracellular fluids and in the cytoplasm of a majority of human cells, has been recently implicated in a variety of both physiological and pathological processes including its involvement in modulating inflammatory responses. Although the role of gelsolin in diseases like asthma has not been well demonstrated, it was found that human airway epithelial cells treated with IL-4 secreted gelsolin and increased gelsolin protein was observed in the bronchoalveolar lavage (BAL) fluid from patients with asthma.

In a new study published in the American Journal of Physiology-Lung Cellular and Molecular Physiology, Columbia University researchers: Dr. Maya Mikami, Dr.  Gene Yocum and Dr.  Charles Emala together with Dr.  Nicola   Heller from the Johns Hopkins University explored in depth the role of gelsolin in allergic lung inflammation. Their findings show that the genetic absence of gelsolin was protective against house dust mite (HDM) sensitization with resultant reduction in lung inflammation in a mouse model of asthma. The research team observed that following 3 weeks of intranasal HDM antigen, the histological examination of lung sections showed a reduction in the infiltration of mononuclear cells surrounding broncho-vascular bundles in gelsolin-null mice compared to wild-type mice. In addition, BAL cell counts and total protein concentrations in BAL were found to be increased in HDM-treated wild-type mice compared with vehicle-treated controls. Whereas, in HDM-treated gelsolin-null mice BAL cell counts and BAL protein concentrations were not significantly increased.

An important step in revealing the critical biological functions of gelsolin was the generation of transgenic gelsolin-lacking (gsn −/−) mouse models. The authors used the transgenic mouse model to investigate the role of gelsolin in allergic lung inflammation. In their pre-clinical studies, the concentration levels of T helper cell type 2 cytokines IL-4, -5, -9, and -13 in HDM-sensitized wild-type mice were found to be significantly higher compared with vehicle-treated wild-type controls, while HDM-sensitized gelsolin-null mice had significantly reduced concentrations of IL-5, -9, and -13 compared with HDM-sensitized wild-type mice. IL-17A, which is associated with severe refractory asthma and other proinflammatory cytokines, such as IL-1b and TNFa and the chemokine monocyte chemoattractant protein (MCP)-1, which is increased in patients with asthma, were all found to be significantly decreased in HDM-treated gelsolin-null mice compared with HDM-treated wild-type mice.

Compared with vehicle-treated gelsolin-null controls, gelsolin-null mice had a significant increase in IL-1b following HDM sensitization, but IL-1b concentrations were still significantly reduced compared with HDM-treated wild-type mice. Eotaxin, a potent chemoattractant specific to eosinophils and produced mostly by epithelial cells in the gastrointestinal tract and lung was found to be significantly increased to identical levels in both wild-type and gelsolin-null mice following HDM sensitization.

After 2 weeks of intranasal HDM, BAL cell counts were significantly increased in wild-type but not in gelsolin-null mice compared with their intranasal PBS controls. A significant increase in the lymphocytes in BALs was observed in HDM-treated wild-type mice compared with vehicle wild-type controls, however, the increase in HDM-treated gelsolin-null mice was less compared with HDM treated wild-type controls

Wild-type and gelsolin-null mice had similar baseline in vivo central airway resistance. However, following HDM sensitization gelsolin-null mice had significantly less central airway resistances in response to inhaled methacholine compared with wild-type mice.

In conclusion, using a compelling number of animal studies, the authors have demonstrated the pathophysiological effects mediated by gelsolin expression, suggesting therapeutic regulation of gelsolin expression has the potential to be a new therapeutic strategy for asthma. Further studies have been recommended to investigate the particular cell types involved in reducing allergic lung inflammation in gelsolin null mice, so as to identify possible cytokine and cellular treatment targets in asthma.