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Local secretion of urocortin 1 promotes microvascular permeability during lipopolysaccharide-induced inflammation.

ABSTRACT: 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-R(1) and CRH-R(2). CRH-R(1) receptor blockade exacerbated, whereas CRH-R(2) 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-R(2) receptor and acts independently of the c-JUN N-terminal kinase signal transduction pathway.

SUBMITTER: Cureton EL

PROVIDER: S-EPMC2795720 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Local secretion of urocortin 1 promotes microvascular permeability during lipopolysaccharide-induced inflammation.

Cureton Elizabeth L EL Ereso Alexander Q AQ Victorino Gregory P GP Curran Brian B Poole Daniel P DP Liao Min M Harken Alden H AH Bhargava Aditi A

Endocrinology 20091009 12

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 per ...[more]

PMID: 19819946

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Project description:Methicillin-resistant Staphylococcus aureus (MRSA) sepsis is a severe condition associated with vascular leakage and poor prognosis. The hemodynamic management of sepsis targets hypotension, but there is no specific treatment available for vascular leakage. Arginine vasopressin (AVP) has been used in sepsis to promote vasoconstriction by activating AVP receptor 1 (V1R). However, recent evidence suggests that increased fluid retention may be associated with the AVP receptor 2 (V2R) activation worsening the outcome of sepsis. Hence, we hypothesized that the inhibition of V2R activation ameliorates the severity of microvascular hyperpermeability during sepsis. The hypothesis was tested using a well-characterized and clinically relevant ovine model of MRSA pneumonia/sepsis and in vitro assays of human lung microvascular endothelial cells (HMVECs). in vivo experiments demonstrated that the treatment of septic sheep with tolvaptan (TLVP), an FDA-approved V2R antagonist, significantly attenuated the sepsis-induced fluid retention and markedly reduced the lung water content. These pathological changes were not affected by the treatment with V2R agonist, desmopressin (DDAVP). Additionally, the incubation of cultured HMVECs with DDAVP, and DDAVP along with MRSA significantly increased the paracellular permeability. Finally, both the DDAVP and MRSA-induced hyperpermeability was significantly attenuated by TLVP. Subsequent protein and gene expression assays determined that the V2R-induced increase in permeability is mediated by phospholipase C beta (PLCβ) and the potent permeability factor angiopoietin-2. In conclusion, our results indicate that the activation of the AVP-V2R axis is critical in the pathophysiology of severe microvascular hyperpermeability during Gram-positive sepsis. The use of the antagonist TLVP should be considered as adjuvant treatment for septic patients. The results from this clinically relevant animal study are highly translational to clinical practice.

Dataset Information

Local secretion of urocortin 1 promotes microvascular permeability during lipopolysaccharide-induced inflammation.

Publications

Local secretion of urocortin 1 promotes microvascular permeability during lipopolysaccharide-induced inflammation.

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