Bluetongue virus and double-stranded RNA increase human vascular permeability: role of p38 MAPK.
Endothelial cell (EC) involvement in viral hemorrhagic fevers has been clearly established. However, virally activated mechanisms leading to endothelial activation and dysfunction are not well understood. Several different potential mechanisms such as direct viral infection, alterations in procoagulant/anticoagulant balance, and increased cytokine production have been suggested. We utilized a model of EC barrier dysfunction and vascular endothelial leakage to explore the effect of bluetongue virus (BTV), a hemorrhagic fever virus of ruminants, on human lung endothelial cell barrier properties. Infection of human lung EC with BTV induced a significant and dose-dependent decrease in trans-endothelial electrical resistance (TER). Furthermore, decreases in TER occurred in conjunction with cytoskeletal rearrangement, suggesting a direct mechanism for viral infection-mediated endothelial barrier disruption. Interestingly, double-stranded RNA (dsRNA) mimicked the effects of BTV on endothelial barrier properties. Both BTV- and dsRNA-induced endothelial barrier dysfunction was blocked by treatment with a pharmacological inhibitor of p38 MAPK. The induction of vascular permeability by dsRNA treatment or BTV infection was concomitent with induction of inflammatory cytokines. Taken together, our data suggest that the presence of dsRNA during viral infections and subsequent activation of p38 MAPK is a potential molecular pathway for viral induction of hemorrhagic fevers. Collectively, our data suggest that inhibition of p38 MAPK may be a possible therapeutic approach to alter viral-induced acute hemorrhagic diseases.
Chiang
Eddie T
ET
University of Chicago, Pritzker School of Medicine, Chicago, Illinois 60637, USA.
Persaud-Sawin
Dixie-Ann
DA
Kulkarni
Sandhya
S
Garcia
Joe G N
JG
Imani
Farhad
F
D001820:Bluetongue virus / Q000472:pathogenicity*; D002199:Capillary Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics; D003599:Cytoskeleton / Q000378:metabolism; D004730:Endothelium, Vascular / Q000473:pathology / Q000821:virology*; D005786:Gene Expression Regulation; D006482:Hemorrhagic Fevers, Viral / Q000209:etiology / Q000473:pathology; D006801:Humans; D008168:Lung / Q000473:pathology / Q000821:virology; D012330:RNA, Double-Stranded / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D016207:Cytokines; D012330:RNA, Double-Stranded; D048051:p38 Mitogen-Activated Protein Kinases