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Local Secretion of Urocortin 1 Promotes Microvascular Permeability during Lipopolysaccharide-Induced Inflammation

Department of Surgery (E.L.C., A.Q.E., G.P.V., B.C., A.H.H.) East Bay Program, University of California, San Francisco, San Francisco, California 94143-0660; and Center for Neurobiology of Digestive Diseases (D.P.P., M.L., A.B.), Department of Surgery, University of California, San Francisco, San Francisco, California 94602

Address all correspondence and requests for reprints to: Aditi Bhargava, Ph.D., Department of Surgery, Center for Neurobiology of Digestive Diseases, 513 Parnassus Avenue, Room S1268, University of California, San Francisco, Box 0660, San Francisco, California 94143. E-mail: aditi.bhargava{at}ucsfmedctr.org; or Gregory P. Victorino, M.D., F.A.C.S., Department of Surgery, University of California, San Francisco-East Bay, 1411 East 31st Street, Oakland, California 94602. E-mail: victorinog{at}surgery.ucsf.edu.

Urocortin 1 (Ucn1) is a neuropeptide that regulates vascular tone and is implicated in both the vascular and immune cell-mediated responses to inflammation. The role of Ucn1 in regulating microvascular permeability has not been determined. We hypothesized that local Ucn1 release promotes microvascular permeability and that this effect augments the local gastrointestinal vascular response to lipopolysaccharide (LPS)-induced systemic inflammation. We measured hydraulic (L_p) and macromolecule permeability in mesenteric venules. We show that a continuous infusion of 10^–7 M Ucn1 in a postcapillary venule increased L_p 2-fold over baseline, as did LPS-induced inflammation. However, simultaneous infusion of Ucn1 and LPS markedly increased L_p by 7-fold. After local knockdown of Ucn1 using RNA interference, infusion of Ucn1 with LPS resulted in return to 2-fold increase, confirming that Ucn1 synergistically augments hydraulic permeability during inflammation. LPS and Ucn1 treatment also resulted in increased numbers of interstitial microspheres, which colocalized with CD31⁺ immune cells. Ucn1 activity is mediated through two receptor subtypes, CRH-R₁ and CRH-R₂. CRH-R₁ receptor blockade exacerbated, whereas CRH-R₂ receptor blockade decreased the LPS-induced increase in L_p. Finally, treatment with the c-JUN N-terminal kinase (JNK) antagonist SP600125 during infusion of LPS, but not Ucn1, decreased L_p. These findings suggest that Ucn1 increases microvascular permeability and acts synergistically with LPS to increase fluid and macromolecule losses during inflammation. Knockdown of endogenous Ucn1 during inflammation attenuates synergistic increases in L_p. Ucn1’s effect on L_p is partially mediated by the CRH-R₂ receptor and acts independently of the c-JUN N-terminal kinase signal transduction pathway.