Effect of Insulin-Like Growth Factor Blockade on Hyperoxia-Induced Lung Injury

Abstract

Insulin-like growth factor (IGF)-1 is increased in different models of acute lung injury, and is an important determinant of survival and proliferation in many cells. We previously demonstrated that treatment of mice with IGF-1 receptor-blocking antibody (A12) improved early survival in bleomycin-induced lung injury. We have now examined whether administration of A12 improved markers of lung injury in hyperoxia model of lung injury. C57BL/6 mice underwent intraperitoneal administration of A12 or control antibody (keyhole limpet hemocyanin [KLH]), then were exposed to 95% hyperoxia for 88-90 hours. Mice were killed and bronchoalveolar lavage (BAL) and lung tissue were obtained for analysis. Hyperoxia caused a significant increase in IGF levels in BAL and lung lysates. Peripheral blood neutrophils expressed IGF-1R at baseline and after hyperoxia. BAL neutrophils from hyperoxia-treated mice and patients with acute lung injury also expressed cell surface IGF-1R. A12-treated mice had significantly decreased polymorphonuclear cell (PMN) count in BAL compared with KLH control mice (P ¼ 0.02). BAL from A12-treated mice demonstrated decreased PMN chemotactic activity compared with BAL from KLH-treated mice. Pretreatment of PMNs with A12 decreased their chemotactic response to BAL from hyperoxiaexposed mice. Furthermore, IGF-1 induced a dose-dependent chemotaxis of PMNs. There were no differences in other chemotactic cytokines in BAL, including CXCL1 and CXCL2. In summary, IGF blockade decreased PMN recruitment to the alveolar space in a mouse model of hyperoxia. Furthermore, the decrease in BAL PMNs was at least partially due to a direct effect of A12 on PMN chemotaxis.Keywords: insulin-like growth factor; hyperoxia-induced lung injury; neutrophils Insulin-like growth factor (IGF)-1 is an important prosurvival factor for many different cell types (1, 2). The IGF pathway can be protective of injury (3) or worsen injury (4, 5), depending on the organ system and the insult. The biological effects of IGF-1 are mediated through interactions with the cell surface receptor, IGF-1 receptor 1R (IGF-1R). We previously demonstrated that mice treated with blocking antibody to IGF-1R, the primary receptor for IGF-1, had improved early survival after bleomycin, as well as improved late resolution of fibrosis (4). The intratracheal administration of bleomycin to mice produces acute lung injury by a mechanism that involves free radical formation and oxidant stress. Although mechanistically different, hyperoxia also induces acute lung injury in mice through generation of reactive oxygen species. Mice heterozygous for IGF-1R have increased resistance to oxidative stress (6, 7). Both IGF and its receptor, IGF-1R, are up-regulated in the lung during hyperoxia and subsequent recovery phase (8). Several studies have demonstrated a role of IGF in the proliferative response of epithelial cells and fibroblasts during hyperoxia-induced lung injury (8,9). In this study. we asked whether we would see differences in lung injury in a mechanistically ...

DAMP Molecule S100A9 Acts as a Molecular Pattern to Enhance Inflammation during Influenza A Virus Infection: Role of DDX21-TRIF-TLR4-MyD88 Pathway

“…in lung homogenate (Figure S9B). Thus, anti-S100A9 antibody could effectively block lung-localized S100A9 during IAV infection [49], [71], [72]. The clinical significance of utilizing neutralizing antibody is obvious from possible passive immunization with S100A9 antibody as a new therapeutic strategy to control lung inflammation and associated lung disease during IAV infection.…”

Hsp90 regulation of fibroblast activation in pulmonary fibrosis

“…Hsp90 inhibitors, such as STA-9090, inhibit proliferation and induce apoptosis in K-Ras-, HER2/neu-, and EGFR-mutant non-small-cell lung cancer cell lines (26), suggesting a role for Hsp90 in different signaling pathways that converge to cell proliferation. IGF1 and SPHK1 have been shown to be upregulated in response to TGF-β stimuli in lung fibroblasts, and blockade of the above gene expression resulted in abrogation of fibroblast proliferation and reduced pulmonary fibrosis in the bleomycin-induced fibrosis mouse model (87)(88)(89). Similarly, MYCN, a known regulator of lung progenitor cell proliferation and differentiation during lung development, is upregulated in TGF-α-induced pulmonary fibrosis (15,90).…”

Insulin-Like Growth Factor-1 Signaling in Lung Development and Inflammatory Lung Diseases

“…Among IGFBPs, IGFBP-2, IGFBP-3, and IGFBP-5 mRNA increased during hyperoxia-induced injury, and IGFBP-5 mRNA is also elevated during the recovery phase [ 74 ]. Hyperoxia significantly increases IGF-1 levels in BALF and mouse lung lysates, as well as IGF-1R-positive neutrophils in peripheral blood and in BALF [ 75 ]. IGF-1 induced a dose-dependent chemotaxis of polymorphonuclear cells to the alveolar space, which is decreased by systemic pretreatment of an IGF-1R antibody in hyperoxia-injured mice [ 75 ].…”