RIG-like Helicase Innate Immunity Inhibits Vascular Endothelial Growth Factor Tissue Responses via a Type I IFN–dependent Mechanism

Aryl hydrocarbon receptor agonists upregulate VEGF secretion from bronchial epithelial cells

“…Furthermore, as compared with primary BECs from normal subjects, the primary BECs from asthmatic patients secreted The lung is one of the organs with high level of basal VEGF expression and activity. Serving as an endothelial cell survival factor, VEGF is important in maintaining normal pulmonary cellular homeostasis and alveolar structure [3]. VEGF may enhance respiratory antigen sensitization and T H 2 inflammation, increase the number of activated dendritic cells, and induce an asthma-like phenotype with eosinophilic inflammation, parenchymal and vascular remodeling, subepithelial fibrosis, edema, mucus metaplasia, myocyte hyperplasia, and airway hyper-responsiveness.…”

“…Chronic airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), are characterized by airway remodeling; vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis and vascular remodeling, important components of airway remodeling [1][2][3][4]. Significantly elevated VEGF levels in serum and bronchoalveolar lavage (BAL) fluid have been noted in patients with asthma and COPD, and the levels have been correlated to airway hyper-responsiveness in asthma and acute exacerbation of COPD [5][6][7].…”

A Synthetic TLR3 Ligand Mitigates Profibrotic Fibroblast Responses by Inducing Autocrine IFN Signaling

“…Lupus nephritis in the NZW/B mice was exacerbated by Poly I:C, and the inflammatory effects were mediated by endogenous IFN, and accumulation of alternately activated macrophages in the kidney (33). In contrast, Poly I:C can also down-regulate inflammation in murine arthritis (34) and other models of inflammation (35). Interestingly, Poly I:C-induced inflammation is generally associated with only a modest degree of fibrosis.…”

“…However, Poly I:C triggers activation of multiple pattern recognition receptors, including RIG-1 and MDA5, and under certain conditions the TLR3-independent cellular response predominates. For example, inhibition of VEGF-mediated responses in transgenic mice by Poly I:C involved a TLR3-independent RIG-1 recognition mechanism (35). Consistent with these observations, we demonstrate that the anti-fibrotic effects elicited by Poly I:C in fibroblasts are largely TLR3-independent and are mediated through both RIG-1 and MDA5.…”

Update in Chronic Obstructive Pulmonary Disease 2011

“…Mutations of the receptor tyrosine kinase c-kit are associated with an emphysema-like disease in mice, and the c-kit inhibitor imatinib was shown to inhibit epithelial clonal expansion (42). Defective function of another growth factor, vascularendothelial growth factor (VEGF), has been been implicated on the pathogenesis of emphysema, and virus infections (influenza and respiratory syncytial virus), as well as the virus mimic poly (I:C), appear to inhibit VEGF signaling in mice (43). A reduction in VEGF receptors was seen in adiponectin knock-out mice, which develop emphysema and have systemic inflammation, weight loss, osteoporosis, and endothelial cell dysfunction, thus providing a link to COPD comorbidities (44).…”