β-Adrenoceptor Agonists Attenuate Thrombin-Induced Impairment of Human Lung Endothelial Cell Barrier Function and Protect the Lung Vascular Barrier during Resuscitation from Hemorrhagic Shock.

β-adrenoceptor (β-AR) agonists are known to antagonize thrombin-induced impairment (TII) of bovine and ovine lung endothelial barrier function. The effects of adrenoceptor agonists and other vasoactive agents on human lung microvascular endothelial cell (HULEC-5a) barrier function upon thrombin exposure have not been studied. Furthermore, it is unknown whether the in vitro effects of adrenoceptor agonists translate to lung protective effects in vivo.

Ethanol promotes protease activated receptor 1: Chemokine (C-X-C motif) receptor 4 heteromerization and enhances thrombin-induced impairment of human lung endothelial cell barrier function.

Ethanol enhances the propensity of PAR1 and CXCR4 to form heteromers. Ethanol increases PAR1:CXCR4 heteromer expression in human lung microvascular endothelial cells (HULEC-5a). Ethanol enhances the efficacy of PAR1 to activate Gα upon thrombin stimulation in cells co-expressing CXCR4.

Chemokine receptor hetero-oligomers regulate monocyte chemotaxis.

It is known that stress influences immune cell function. The underlying molecular mechanisms are unclear. We recently reported that many chemokine receptors (CRs) heteromerize with α-adrenoceptors (α-ARs) through which CRs are regulated.

G protein activation via chemokine (C-X-C motif) receptor 4 and α -adrenoceptor is ligand and heteromer-dependent.

It is unknown whether heteromerization between chemokine (C-X-C motif) receptor 4 (CXCR4), atypical chemokine receptor 3 (ACKR3) and α -adrenoceptor (α -AR) influences effects of the CXCR4/ACKR3 agonist chemokine (C-X-C motif) ligand 12 (CXCL12) and the noncognate CXCR4 agonist ubiquitin on agonist-promoted G protein activation. We provide biophysical evidence that both ligands stimulate CXCR4-mediated Gαi activation. Unlike CXCL12, ubiquitin fails to recruit β-arrestin.

Effects of chemokine (C-C motif) receptor 2 and 3 antagonists in rat models of hemorrhagic shock.

Systemic concentrations of chemokine CCL2, an agonist at chemokine receptors CCR2/3/5, have been associated with hemodynamic instability after traumatic-hemorrhagic shock. We reported previously that the CCR2 antagonist INCB3284 prevents cardiovascular collapse and reduces fluid requirements after 30min of hemorrhagic shock (HS), whereas the CCR5 antagonist Maraviroc was ineffective. The effects of CCR3 blockade after HS are unknown and information on the therapeutic potential of INCB3284 after longer periods of HS and in HS models in the absence of fluid resuscitation (FR) is lacking.