Activation of Toll-like receptor 2 impairs hypoxic pulmonary vasoconstriction in mice

Abstract

Toll-like receptors (TLRs) mediate inflammation in sepsis, but their role in sepsis-induced respiratory failure is unknown. Hypoxic pulmonary vasoconstriction (HPV) is a unique vasoconstrictor response that diverts blood flow away from poorly ventilated lung regions. HPV is impaired in sepsis and after challenge with the TLR4 agonist lipopolysaccharide (LPS). Unlike TLR4 agonists, which are present only in Gram-negative bacteria, TLR2 agonists are ubiquitously expressed in all of the major classes of microorganisms that cause sepsis, including both Gram-positive and Gram-negative bacteria and fungi. We tested the hypothesis that (S)-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-N-palmitoyl-(R)-Cys-(S)-Ser(S)-Lys(4)-OH, trihydrochloride (Pam3Cys), a TLR2 agonist, impairs HPV and compared selected pulmonary and systemic effects of Pam3Cys vs. LPS. HPV was assessed 22 h after challenge with saline, Pam3Cys, or LPS by measuring the increase in the pulmonary vascular resistance of the left lung before and during left lung alveolar hypoxia produced by left mainstem bronchus occlusion (LMBO). Additional endpoints included arterial blood gases during LMBO, hemodynamic parameters, weight loss, temperature, physical appearance, and several markers of lung inflammation. Compared with saline, challenge with Pam3Cys caused profound impairment of HPV, reduced systemic arterial oxygenation during LMBO, weight loss, leukopenia, and lung inflammation. In addition to these effects, LPS-challenged mice had lower rectal temperatures, metabolic acidosis, and were more ill appearing than Pam3Cys-challenged mice. These data indicate that TLR2 activation impairs HPV and induces deleterious systemic effects in mice and suggest that TLR2 pathways may be important in sepsis-induced respiratory failure.

Pivotal role of glutamine synthetase in ammonia detoxification

“…Humans and rats secrete 50% of the ammonia produced by the kidneys into the systemic circulation. (5,22) Under standard conditions, as in this study, ammonia secretion into the renal vein of mice amounts to 10 lmol/hour, but the 4-fold to 7-fold increased renal ammonia production and secretion during metabolic acidosis, (14,15) as develops during, e.g., septicemia, (23) would most likely render GS-KO/L or GS-KO/M mice hyperammonemic.…”

ERK5 Protein Promotes, whereas MEK1 Protein Differentially Regulates, the Toll-like Receptor 2 Protein-dependent Activation of Human Endothelial Cells and Monocytes

“…The endothelium participates in the septic response through the production of inflammatory mediators, up-regulation of adhesion molecules, modulation of coagulation pathways, and alteration of barrier functions (1,2). We previously found that bacterial lipoprotein TLR2 agonists, which are ubiquitously expressed by all bacteria that cause sepsis, induce endothelial inflammation and neutrophil adhesion to EC monolayers, increase lung neutrophil trafficking and respiratory dysfunction, and modulate the activity of several coagulation pathway intermediaries (16,20,45). The present studies delved into the signaling pathways involved in the TLR2-dependent activation of endothelial inflammation and modulation of coagulation pathway intermediaries.…”

Bacterial Lipoprotein TLR2 Agonists Broadly Modulate Endothelial Function and Coagulation Pathways In Vitro and In Vivo

“…We reported that TLR2 activation modulates inflammatory effects of other TLR agonists, induces systemic, lung and myocardial inflammation in mice, and reduces contractility of cardiac myocytes in vitro (29–32). We have also found that TLR2 activation in vivo causes impaired vasoconstrictive responses to alveolar hypoxia and reduced arterial blood oxygenation (PaO 2 ) in mice (33). …”