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

Abstract

Airway smooth muscle hyperresponsiveness associated with chronic airway inflammation leads to the typical symptoms of asthma including bronchoconstriction and wheezing. Asthma severity is associated with airway inflammation; therefore reducing airway inflammation is an important therapeutic target. Gelsolin is an actin capping and severing protein that has been reported to be involved in modulation of the inflammatory response. Using mice genetically lacking gelsolin, we evaluated the role of gelsolin in the establishment of house dust mite (HDM) antigen-induced allergic lung inflammation. The genetic absence of gelsolin was found to be protective against HDM sensitization, resulting in reduced lung inflammation, inflammatory cytokines and Muc5AC protein in bronchoalveolar lavage (BAL) fluid. The number of eosinophils, lymphocytes and interstitial macrophages in the BAL were increased after HDM sensitization in wild type mice, but were attenuated in gelsolin null mice. The observed attenuation of inflammation may be partly due to delayed migration of immune cells, because the reduced eosinophils in the BALs from gelsolin null mice compared to controls occurred despite similar amounts of the chemoattractant eotaxin. Splenic T cells demonstrated similar proliferation rates, but ex vivo alveolar macrophage migration was delayed in gelsolin null mice. In vivo, the reduced lung inflammation after HDM sensitization in gelsolin null mice was associated with significantly diminished airway resistance to inhaled methacholine compared with HDM-treated wild type mice. Our results suggest that modulation of gelsolin expression or function in selective inflammatory cell types that modulate allergic lung inflammation could be a therapeutic approach for asthma.

Chronic allergic lung inflammation negatively influences neurobehavioral outcomes in mice

“…Next, we sought to confirm inflammation in the lungs after long-term intranasal HDM sensitization. We have previously demonstrated that 10 days to 3 weeks of intranasal HDM administration can cause significant lung inflammation as assessed by histological changes, bronchoalveolar lavage (BAL) cell count, BAL protein concentrations and cytokine measurements in lung digests [ 19 ]. In the current study, we extended the duration of HDM administration to 6 weeks to mimic the chronic status of lung inflammation.…”

“…As many as 50% of asthmatic patients are sensitized with HDM [ 18 ]. Using an HDM mouse model, our group previously showed that 10 days to 3 weeks of intranasal HDM administration causes significant lung inflammation demonstrated by histological changes, increased cell counts in bronchoalveolar lavages (BAL), and increased protein concentrations in BAL as well as increased IL-1β and TNF-α in lung digests [ 19 ]. By extending the duration of HDM sensitization to mimic chronic states of allergic lung inflammation, we sought to test our hypothesis that chronic allergic lung inflammation causes inflammation in the brain, likely through cytokine-mediated disruption of the blood brain barrier, causing mast cell activation, resulting in neurobehavioral changes in mice.…”