Involvement of Toll-Like Receptor 4 in Decreased Vasopressor Response Following Trauma/Hemorrhagic Shock.

Autor:	Mazor R; Department of Anesthesiology and Critical Care, University of California San Diego/VA San Diego Healthcare System, La Jolla, CA., Dos Santos F; Department of Anesthesiology and Critical Care, University of California San Diego/VA San Diego Healthcare System, La Jolla, CA.; Department of Bioengineering, University of California San Diego, La Jolla, CA., Li JB; Department of Anesthesiology and Critical Care, University of California San Diego/VA San Diego Healthcare System, La Jolla, CA.; Department of Bioengineering, University of California San Diego, La Jolla, CA., Aletti F; Department of Anesthesiology and Critical Care, University of California San Diego/VA San Diego Healthcare System, La Jolla, CA., Schmid-Schonbein G; Department of Bioengineering, University of California San Diego, La Jolla, CA., Kistler EB; Department of Anesthesiology and Critical Care, University of California San Diego/VA San Diego Healthcare System, La Jolla, CA.
Jazyk:	angličtina
Zdroj:	Critical care explorations [Crit Care Explor] 2021 Jul 06; Vol. 3 (7), pp. e0469. Date of Electronic Publication: 2021 Jul 06 (Print Publication: 2021).
DOI:	10.1097/CCE.0000000000000469
Abstrakt:	Refractory vascular failure due to the inability of vascular smooth muscle to respond to vasoconstrictors such as phenylephrine is a final common pathway for severe circulatory shock of any cause, including trauma/hemorrhagic shock. Increased inflammation, Toll-like receptor 4 activation, and decreased response of the alpha-1 adrenergic receptors which control vascular tone have been reported in trauma/hemorrhagic shock. Hypothesis: In trauma/hemorrhagic shock, Toll-like receptor 4 activation contributes to vascular failure via decreased bioavailability of adrenergic receptors. Design and Measurements: Trauma/hemorrhagic shock was induced in Wistar rats (laparotomy combined with mean arterial pressure at 40 mm Hg for 90 min followed by 2 hr resuscitation with Lactated Ringers solution). To inhibit Toll-like receptor 4, resatorvid (TAK-242) and resveratrol were used, and plasma was collected. Smooth muscle cells were incubated with lipopolysaccharide (10 ng/mL) or plasma. Inflammatory cytokines were screened using dot-blot. Toll-like receptor 4 and nuclear factor κB activation and cellular localization of the alpha-1 adrenergic receptor were measured by immunofluorescence imaging and Western blot analysis. Clustered regularly interspaced short palindromic repeats/Cas9 was used to knock out Toll-like receptor 4, and calcium influx following stimulation with phenylephrine was recorded. Main Results: Trauma/hemorrhagic shock caused a decreased response to phenylephrine, whereas Toll-like receptor 4 inhibition improved blood pressure. Trauma/hemorrhagic shock plasma activated the Toll-like receptor 4/nuclear factor κB pathway in smooth muscle cells. Double labeling of Toll-like receptor 4 and the alpha-1 adrenergic receptor showed that these receptors are colocalized on the cell membrane. Activation of Toll-like receptor 4 caused cointernalization of both receptors. Calcium influx was impaired in cells incubated with trauma/hemorrhagic shock plasma but restored when Toll-like receptor 4 was knocked out or inhibited. Conclusions: Activation of the Toll-like receptor 4 desensitizes vascular smooth muscle cells to vasopressors in experimental trauma/hemorrhagic shock by reducing the levels of membrane alpha-1 adrenergic receptor. (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)
Databáze:	MEDLINE
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