Angiogenic Cytokine Induction in Lung Injury Response to 2‐Chloroethyl Ethyl Sulfide, a Mustard Gas Analog

Abstract

We reported earlier that guinea pigs exposed to 2-chloroethyl ethyl sulfide (CEES) as a mustard gas analog, accumulate inflammatory cytokines TNF-α,IL-1αINFγand chemokines, Eotaxin and MIP-1δin the lung, at higher levels within 1 h. Since angiogenesis may play a role, in inflammation and pathophysiology of tissue remodeling, we evaluated the early induction profile of angiogenic cytokines and selected target genes using cytokine antibody arrays. VEGF and bFGF levels showed 1.5-fold increase within 1 h of exposure. However, while VEGF remained high after one day, bFGF level was decreased. We detected 2-fold increase of numerous pro-angiogenic cytokines, members of FGF and TGF-β family, PDGF-BB, interleukins (IL-1, IL-4) and TNF-α within 1hr, most of which induce expression of VEGF, a potent angiogenic factor. Essential mediators in angiogenesis and tissue remodeling such as TSP, TIMP2 (1hr.) and uPAR (1 day) were increased by 1.7-fold. Increase in VEGF receptors Flk-1 and Flt-1and MMP-2 were also detected by Western blot analysis in 1 day. Our results suggest a disruption in vascular quiescence maintained by the balance between stimulators and inhibitors of angiogenesis as early as 1hr. post CEES. Regulated by various proinflamatory cytokines, VEGF may thus play an essential role in inducing chronic inflammation, fibrosis, and cancer following lung injury. (Supported by US Army Grant DAMD 17-03-2-0054)