Inhibition of Lipopolysaccharide-Induced Prostaglandin E₂Production and Inflammation by the Na⁺/H⁺Exchanger Inhibitors

Abstract

We analyzed the effects of the Na ϩ /H ϩ exchanger (NHE) inhibitor 3,5-diamino-6-chloro-N-(diaminomethylidene)pyrazine-2-carboxamide hydrochloride (amiloride) and its analogs 5-(N,Ndimethyl)-amiloride (DMA) and 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) on the lipopolysaccharide (LPS)-induced production of prostaglandin (PG) E 2 in vitro and in vivo. In the mouse macrophage-like cell line RAW 264, these inhibitors suppressed the LPS (1 g/ml)-induced production of PGE 2 at 8 h in a concentration-dependent manner. They also reduced the LPS-induced release of arachidonic acid from membrane phospholipids at 4 h and the LPS-induced increase in the level of cyclooxygenase (COX)-2 protein at 6 h, but not the level of COX-2 mRNA at 3 h. The LPS-induced phosphorylation of mitogen-activated protein kinases and degradation of inhibitor of B-␣ were not inhibited by these drugs. In an air pouch-type LPS-induced inflammation model in mice 30 mg/kg amiloride and 10 mg/kg EIPA as well as the COX inhibitor indomethacin (10 mg/kg), significantly reduced the level of PGE 2 in the pouch fluid at 8 h and the vascular permeability from 4 to 8 h. The accumulation of pouch fluid and leukocytes in the pouch fluid at 8 h was significantly inhibited by amiloride and EIPA but not by indomethacin. These findings suggested that the NHE inhibitors suppress the production of PGE 2 through inhibiting the release of arachidonic acid and the increase in COX-2 protein levels and thus induce anti-inflammatory activity.

Enhancement of nickel elution by lipopolysaccharide-induced inflammation

“…In addition, the NHE inhibitor also inhibited bone resorption and acidification [32], although the molecular mechanisms involved are not completely clear. However, amiloride inhibits the LPS-induced activation of cells [33,34]. Taken together, the molecular mechanisms of the elution of Ni might be similar to those behind the resorption of bone by osteoclasts.…”

Basolateral LPS inhibits NHE3 and HCO3−absorption through TLR4/MyD88-dependent ERK activation in medullary thick ascending limb

“…LPS inhibits NHE3 when exchanger activity is studied independently of the activity of other transporters and in the absence of a change in the driving force for the exchanger, indicating that the LPS-induced ERK pathway is coupled directly to inhibition of NHE3. The ubiquitously expressed Na ϩ /H ϩ exchanger isoform NHE1 has been identified as a target for modulation by LPS in several cell types (9,40,52,56,65). Thus LPS-induced ERK activation leads to a decrease in the intrinsic activity of individual transporters within the membrane and/or alters the subcellular distribution of NHE3 to decrease the number of transporters in active apical membrane domains.…”

Acetylbritannilactone Inhibits Neointimal Hyperplasia after Balloon Injury of Rat Artery by Suppressing Nuclear Factor-κB Activation

“…It has been reported that prostaglandins might influence the development of restenosis and intimal hyperplasia (Connolly et al, 2002). PGE 2 enhanced platelet aggregation, chemotaxis of leukocytes, vascular permeability, and vascular cell adhesion molecule expression, thus resulting in serious damage in the arterial walls (Roviezzo et al, 2005;Chen et al, 2006;Kamachi et al, 2007). Therefore, we believe that not only local inflammations but also systemic inflammations, as measured by serum PGE 2 , play an important part in the development of neointimal hyperplasia.…”