Elsevier

Surgery

Volume 128, Issue 2, August 2000, Pages 198-205
Surgery

Society od University Surgeons
Hypertonic saline solution induces prostacyclin production by increasing cyclooxygenase-2 expression*,**

Presented at the 61st Annual Meeting of the Society of University Surgeons, Toronto, Ontario, Canada, February 10-12, 2000.
https://doi.org/10.1067/msy.2000.107606Get rights and content

Abstract

Background: Previously, we demonstrated that hypertonic saline solution (HTS) and endotoxin (lipopolysaccharide [LPS]) induce prostacyclin (PGI2) production in human endothelial cells. Here, we hypothesized that HTS and LPS may induce PGI2 production by increasing cyclooxygenase (COX) expression. We further examined the activation of p38 and extracellular signal-regulated kinases (ERK) and questioned whether these transduction cascades might mediate COX expression. Methods: Human umbilical vein endothelial cells were stimulated with varying concentrations of NaCl or LPS. Results: HTS and LPS induced prompt activation of both p38 and ERKs that peaked at 30 minutes. HTS and LPS also induced a dose-related increase in COX-2 with maximal expression within 4 to 6 hours; there was no change in COX-1. This correlated with an increase in supernatant PGI2 levels, which became statistically significant for NaCl of more than 40 mmol/L and for all LPS doses. The inhibition of p38 with SB202190 abrogated the osmotic and LPS-induced COX-2 expression and PGI2 production. Inhibition of ERK activation had no effect on COX-2 expression. Conclusions: Hyperosmolarity and LPS induce, in chronologic order, p38 and ERK activation, COX-2 expression, and PGI2 production. Because COX is the rate-limiting enzyme in prostaglandin synthesis, it is likely that the increase in PGI2 production is due to, at least in part, the increased COX-2 expression. The data also suggest that p38 mitogen-activated protein kinase is involved in the signaling cascade for COX-2 expression. (Surgery 2000;128:198-205.)

Section snippets

Reagents

Escherichia coli 0111:B4 LPS (Sigma, St Louis, Mo) was dissolved in phosphate-buffered saline solution with 0.1% triethylamine at 1 mg/mL. PD 98059 (Calbiochem-Novabiochem, La Jolla, Calif) was dissolved in dimethyl sulfoxide to give a concentration of 50 mmol/L. SB202190 (Calbiochem) was dissolved in dimethyl sulfoxide to give a concentration of 10 mmol/L. Crystalline NaCl (J.T. Baker, Phillipsburg, NJ) was dissolved in sterile pyrogen-free water at a concentration of 2 mol. For HTS

Osmotic stress–activated p38 and ERK MAPK in HUVECs

We studied the osmotic stress activation of p38 and ERK by increasing the NaCl concentration in the culture media. The activation status of p38 and ERK was assessed by Western blot analyses, with their respective dual phospho-specific antibodies that recognize only the activated species of p38 or ERK. Equal protein loading was confirmed by Western blot analyses with an antibody to the total ERK MAPK. Osmotic stress activated both p38 and ERK with a similar pattern of activation (Fig 1). p38 and

Discussion

There is increasing evidence that some of the beneficial effects observed with hypertonic saline solution resuscitation may be due to a direct effect of increasing osmolarity on cell function, such as altering monocyte cytokine production and T-cell proliferation.14, 15 Previous and current observations from our laboratory support such a role; hypertonicity (specifically, an increase in NaCl concentration above 40 mmol/L) induced pronounced PGI2 production. Although the absolute fold increase

References (24)

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*

Supported by National Institutes of Health Grants GM45873 and GM07037.

**

Reprint requests: Saman Arbabi, MD, Harborview Medical Center, Department of Surgery, University of Washington, Box 359796, 325 Ninth Ave, Seattle, WA 98104.

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