Hyperosmolarity attenuates TNF-α-mediated proinflammatory activation of human pulmonary microvascular endothelial cells.
Firm neutrophil (PMN)-endothelial (EC) adhesion is crucial to the PMN-mediated hyperinflammation observed in acute lung injury. Hypertonic saline (HTS) used for resuscitation of hemorrhagic shock has been associated with a decreased incidence of PMN-mediated lung injury/acute respiratory distress syndrome. We hypothesize that physiologically accessible hypertonic incubation (170 vs. 140 mM, osmolarity ranging from 360 to 300 mOsm/L) inhibits proinflammatory activation of human pulmonary microvascular endothelial cells (HMVECs). Proinflammatory activation of HMVECs was investigated in response to tumor necrosis factor-α (TNF-α), including interleukin 8 (IL-8) release, intercellular adhesion molecule 1 (ICAM-1) surface expression, PMN adhesion, and signaling mechanisms under both isotonic (control) and hypertonic conditions. Hyperosmolarity alone had no effect on either basal IL-8 release or ICAM-1 surface expression but did lead to concentration-dependent decreases in TNF-α-induced IL-8 release, ICAM-1 surface expression, and PMN-HMVEC adhesion. Conversely, HTS activated p38 mitogen-activated protein kinase (MAPK) and enhanced TNF-α activation of p38 MAPK. Despite this basal activation, hyperosmolar incubation attenuated TNF-α-stimulated IL-8 release and ICAM-1 surface expression and subsequent PMN adherence, while p38 MAPK inhibition did not further influence the effects of hyperosmolar conditions on ICAM-1 surface expression. In addition, TNF-α induced nuclear factor-κB DNA binding, but HTS conditions attenuated this by 31% (P < 0.01). In conclusion, HTS reduces PMN-HMVEC adhesion and TNF-α-induced proinflammatory activation of primary HMVECs via attenuation of nuclear factor-κB signaling.
Department of Surgery, Denver Health Medical Center, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado 80045, USA. Anirban.Banerjee@ucdenver.edu
Anirban
A
Banerjee
Ernest E
EE
Moore
Nathan J
NJ
McLaughlin
Luis
L
Lee
Wilbert L
WL
Jones
Jeffrey L
JL
Johnson
Trevor L
TL
Nydam
Christopher C
CC
Silliman
D055371:Acute Lung Injury / Q000209:etiology / Q000517:prevention & control; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008168:Lung / Q000098:blood supply*; D055806:Microvessels / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects; D009994:Osmolar Concentration; D010766:Phosphorylation; D012462:Saline Solution, Hypertonic / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D016209:Interleukin-8; D016328:NF-kappa B; D012462:Saline Solution, Hypertonic; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D048051:p38 Mitogen-Activated Protein Kinases