IGF1R deficiency attenuates acute inflammatory response in a bleomycin-induced lung injury mouse model

Abstract

IGF1R (Insulin-like Growth Factor 1 Receptor) is a tyrosine kinase with pleiotropic cellular functions. IGF activity maintains human lung homeostasis and is implicated in pulmonary diseases such as cancer, ARDS, COPD, asthma and fibrosis. Here we report that lung transcriptome analysis in mice with a postnatally-induced Igf1r gene deletion showed differentially expressed genes with potentially protective roles related to epigenetics, redox and oxidative stress. After bleomycin-induced lung injury, IGF1R-deficient mice demonstrated improved survival within a week. Three days post injury, IGF1R-deficient lungs displayed changes in expression of IGF system-related genes and reduced vascular fragility and permeability. Mutant lungs presented reduced inflamed area, down-regulation of pro-inflammatory markers and up-regulation of resolution indicators. Decreased inflammatory cell presence in BALF was reflected in diminished lung infiltration mainly affecting neutrophils, also corroborated by reduced neutrophil numbers in bone marrow, as well as reduced lymphocyte and alveolar macrophage counts. Additionally, increased SFTPC expression together with hindered HIF1A expression and augmented levels of Gpx8 indicate that IGF1R deficiency protects against alveolar damage. These findings identify IGF1R as an important player in murine acute lung inflammation, suggesting that targeting IGF1R may counteract the inflammatory component of many lung diseases.

Characterization of the acute inflammatory profile and resolution of airway inflammation after Igf1r-gene targeting in a murine model of HDM-induced asthma

“…Preventive induction of Igf1r deficiency in PBS-treated mice led to similar Igf1r- depleted expression to that observed in unchallenged mice of similar age [ 11 ]. In addition, Igf1r and Igf1 levels increased after HDM exposure.…”

“…Right lobes were separated and snap-frozen in liquid nitrogen for quantitative real-time PCR (qRT-PCR) and ELISA analyses. Additionally, femoral bone marrow was isolated as previously described [ 11 ]. Three different sets of mice were used respectively for BALF, histology/molecular analyses and bone marrow cell counts.…”

“…Hematoxylin and eosin (H&E) staining was performed for quantification of inflamed lung areas and airway thickness. Quantification of inflammation was conducted as previously described [ 11 ]. Airway thickness was assessed by means of three different measurements per airway.…”

“…In mice, IGF1 was reported to be a relevant mediator of allergic airway inflammation and remodeling, and that IGFBP3 blocks the specific physiological consequences of this pathology [ 8 – 10 ]. Notably, we have recently reported that IGF1R plays an important role in initiation of the inflammatory response in mice, and the importance of IGF1R in the pathogenesis of murine asthma, mediating both AHR and mucus secretion after chronic HDM exposure [ 11 , 12 ]. Thus, we aimed to further investigate the involvement of IGF1R in allergic airway inflammation.…”

Glutathione Peroxidase 8 (GPX8)-IL6 axis is essential in maintaining breast cancer mesenchymal stem-like state and aggressive phenotype

“…For example, its serves as a cellular substrate to the hepatitis C virus NS3-4A protease (28), and ectopic expression of GPX8 in the rat pancreatic b-cells induces ER stress (29). Our knowledge about GPX8 regulation is still limited, as its expression was found to be regulated by hypoxiainducible factor (HIF1a) (30) and repressed by insulin-like growth factor 1 receptor (IGF1R) in the lung (31). These studies are only starting to reveal some physiological roles of GPX8, but its function in the biology of tumors is still unclear.…”