The Role of High Mobility Group Box1 in Pulmonary Fibrosis

Abstract

High mobility group box1 protein (HMGB1) was originally discovered as a nuclear binding protein, and is known to play an important role in acute lung injury. However, the role of HMGB1 in pulmonary fibrosis has not been addressed. Therefore, we measured the HMGB1 levels in serum and bronchoalveolar lavage fluids (BALF) from patients with idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia, interstitial pneumonia associated with collagen vascular diseases, and hypersensitivity pneumonitis (HP) by enzyme-linked immunosorbent assay. We also assessed the HMGB1 expression in bleomycin-induced pulmonary fibrosis in mice, and examined the effect of anti-HMGB1 antibody and ethyl pyluvate, which inhibits the HMGB1 secretion from alveolar macrophages. In addition, we examined the effect of HMGB1 on fibroblast proliferation, apoptosis, and collagen synthesis in vitro. Serum HMGB1 levels were not significantly increased in interstitial lung diseases compared with control subjects. BALF HMGB1 levels were significantly increased in IPF and HP compared with control subjects. HMGB1 protein was predominantly detected in inflammatory cells and hyperplasic epithelial cells in IPF. In bleomycin-induced pulmonary fibrosis in mice, HMGB1 protein was predominantly up-regulated in bronchiolar epithelial cells at early phase and in alveolar epithelial and inflammatory cells in fibrotic lesions at later phase. Intraperitoneal injection of anti-HMGB1 antibody or ethyl pyluvate significantly attenuated lung inflammation and fibrosis in this model. HMGB1 significantly induced proliferation, but not apoptosis or collagen synthesis on cultured fibroblasts. HMGB1 may be a promising target against pulmonary fibrosis as well as acute lung injury.

HMGB1 contributes to allergen-induced airway remodeling in a murine model of chronic asthma by modulating airway inflammation and activating lung fibroblasts

“…24 In this study, we observed that anti-HMGB1 treatment led to reduced peribronchial collagen deposition as well as total lung collagen content. Our results are consistent with other observational studies, which showed that administration of an anti-HMGB1 antibody reduced the levels of collagen in the lungs in a bleomycin-induced mouse model of pulmonary fibrosis 7 and in an allergen-induced mouse model of chronic asthma. 19 TGF-b1 and MMP-9 have been shown to play important roles in the modulation of lung collagen homeostasis.…”

“…First, we found that HMGB1 can directly induce human lung fibroblast proliferation, which is consistent with a previous report by Hamada et al 7 Additionally, we observed that HMGB1 increases human lung fibroblast migration and a-SMA expression. These results demonstrate that HMGB1 promotes the differentiation of fibroblasts into myofibroblasts, which contributes to ECM protein overproduction and deposition in the form of sub-epithelial fibrosis.…”

“…16 Although Hamada et al 7 reported that treatment with an anti-HMGB1 antibody did not lead to a reduction in TGF-b1 levels in BALF from mice, we detected a significant decrease in TGF-b1 expression levels in mice treated with an anti-HMGB1 antibody treatment compared to the control mice. As HMGB1 promotes the survival of human eosinophils and can enhanced eosinophil chemotaxis, 30 it is reasonable to assume that blocking HMGB1 activity can decrease the number of eosinophils infiltrating into the lung, as suggested by this study and another study.…”

“…We previously reported increased levels of HMGB1 in asthma patients and asthmatic mice. 7,8 In this study, we present additional evidence that HMGB1 may be involved in the pathogenesis of asthma, including airway remodeling. Our finding that anti-HMGB1 treatment inhibits airway remodeling in a mouse model of chronic asthma is consistent with a recent report by Lee et al 19 However, our study identified a different mechanism.…”

“…More interestingly, HMGB1 has been shown to play a pivotal role in pulmonary fibrosis, partly through reduction of fibroblast proliferation and downregulation of interleukin (IL)-1b levels. 7 Furthermore, some researchers have found that HMGB1 promotes secretion of vascular endothelial growth factor (VEGF) 8 and that treatment with anti-HMGB1 antibodies suppresses the activity of matrix metalloproteinase (MMP)-9, 9 both of which are involved in airway remodeling.…”