Gelsolin expression is necessary for the development of modelled pulmonary inflammation and fibrosis

Abstract

Background: Despite intense research efforts, the aetiology and pathogenesis of idiopathic pulmonary fibrosis remain poorly understood. Gelsolin, an actinbinding protein that modulates cytoskeletal dynamics, was recently highlighted as a likely disease modifier through comparative expression profiling and target prioritisation. Methods: To decipher the possible role of gelsolin in pulmonary inflammation and fibrosis, immunocytochemistry on tissue microarrays of human patient samples was performed followed by computerised image analysis. The results were validated in the bleomycin-induced animal model of pulmonary inflammation and fibrosis using genetically-modified mice lacking gelsolin expression. Moreover, to gain mechanistic insights into the mode of gelsolin activity, a series of biochemical analyses was performed ex vivo in mouse embryonic fibroblasts. Results: Increased gelsolin expression was detected in lung samples of patients with idiopathic interstitial pneumonia as well as in modelled pulmonary inflammation and fibrosis. Genetic ablation of gelsolin protected mice from the development of modelled pulmonary inflammation and fibrosis attributed to attenuated epithelial apoptosis. Conclusions: Gelsolin expression is necessary for the development of modelled pulmonary inflammation and fibrosis, while the caspase-3-mediated gelsolin fragmentation was shown to be an apoptotic effector mechanism in disease pathogenesis and a marker of lung injury.Epithelial damage or apoptosis is a common feature of pulmonary pathophysiology, including infection, acute lung injury and interstitial diseases.

Proteome Expression and Carbonylation Changes During Trypanosoma cruzi Infection and Chagas Disease in Rats

“…It is a key regulator of actin filament assembly and disassembly and is involved in maintaining cell structure and motility (49). Increased GSN expression is associated with interstitial fibrosis and inflammation (51), likely because of the GSN-mediated destabilization of cytoskeleton and increased movement of platelets and immune infiltrate, and GSN Ϫ/Ϫ mice are shown to develop decreased pulmonary fibrosis and inflammation (51). In the heart, GSN is shown to catalyze the disassembly and degradation of myocardial proteins (52), and its increased expression is detected in failing human hearts (52).…”

Comparative Proteomic Analysis of Rat Bronchoalveolar Lavage Fluid after Exposure to Zinc Oxide Nanoparticles

“…Our results are consistent with those from previous studies that showed that exposure to ZnO NPs mainly induces lung in ammation and immune response in rats. 3,22) Although S100A8 and S100A9, candidate markers of idiopathic pulmonary brosis and lung cancer, 23,24) were not identi ed, pulmonary surfactant-associated protein D and gelsolin, biomarkers of idiopathic pulmonary brosis, [35][36][37] were signi cantly up-regulated in rat BALF a er ZnO NPs exposure (2.42-and 2.84-fold, respectively). Although it is necessary to further clarify the potential health risks associated with exposure to zinc oxide nanoparticles, the results obtained by gel-based proteomic analysis in this study and those obtained by an LC-based proteomic approach in our previous study 22) indicate that these in ammatory responses might induce idiopathic pulmonary brosis or lung cancer.…”

“…Several studies have shown that the concentration of gelsolin in patients with idiopathic pulmonary brosis or brotic non-speci c interstitial pneumonia is higher than in healthy individuals. 36,37) Although LC-based approach shown many advantages, one of the most important bene t of the gel-based method is that this technology can detect di erent molecular forms. For example, Mitsumoto et al reported that protein deglycase DJ-1 appeared as two di erent major molecular forms on 2DE gel, pI 5.8 (DJ-1/5.8) and pI 6.2 (DJ-1/6.2).…”

Does urinary peptide content differ between COPD patients with and without inherited alpha1-antitrypsin deficiency?

“…Caspase-3-mediated gelsolin fragmentation has been proposed to be an apoptotic effector mechanism in COPD pathogenesis and a marker of lung injury. 32 Alterations in gelsolin expression have been associated with cigarette smoking and different pulmonary diseases such as fibrosis; however, little is known about the role of gelsolin in COPD. [32][33][34] Gelsolin activates PI3K/Akt pathway, 35 which regulates cell growth, proliferation, adhesion, migration and survival.…”

“…32 Alterations in gelsolin expression have been associated with cigarette smoking and different pulmonary diseases such as fibrosis; however, little is known about the role of gelsolin in COPD. [32][33][34] Gelsolin activates PI3K/Akt pathway, 35 which regulates cell growth, proliferation, adhesion, migration and survival. Interestingly, it promotes the differentiation of alveolar epithelial type I and II cells from alveolar epithelial stem cells.…”