Pinaverium Bromide Attenuates Lipopolysaccharide-Induced Excessive Systemic Inflammation via Inhibiting Neutrophil Priming

Abstract

Dominant infiltration of neutrophils is a hallmark of many inflammatory diseases, especially in septic shock. IL-1β as one of the most early released proinflammatory cytokine in neutrophil, plays a pivotal role in the progress of sepsis. In this study, we built a high-throughput–compatible drug screen assay platform based on our newly constructed reporter C57BL/6 mice, pIL1-DsRed, expressing the DsRed gene under the control of the IL-1β promoter. After screening 1200 U.S. Food and Drug Administration–approved compounds, we found that pinaverium bromide (PVB) significantly suppressed the DsRed expression of primed neutrophil and improved the survival rate of mice given LPS in an endotoxin challenge analogous to sepsis, regardless of whether PVB was administered before or after LPS. PVB also protected the liver and lung from LPS-induced damage and reduced organ-specific inflammatory responses. PVB decreased the production of IL-1β, IL-6, and CXCL1 mRNA in the lungs of LPS-treated mice and decreased the serum levels of liver transaminases (alanine aminotransferase and aspartate aminotransferase) at multiple time points and doses tested. PVB can significantly suppress primed neutrophil-specific respiratory bursts and migration as well. Lastly, PVB affected neutrophils’ gene expression and phenotypic changes during neutrophil priming. PVB downregulated GM-CSF–induced expression of CD54 and dectin-2 (markers of fully primed neutrophils) at both mRNA and protein levels during late-phase neutrophil priming. In summary, we demonstrated that PVB can be used as a potential therapeutic agent for sepsis by inhibiting neutrophil priming.

In Vitro Inhibition of Growth, Biofilm Formation, and Persisters of Staphylococcus aureus by Pinaverium Bromide

“…Pinaverium bromide, a gastrointestinal (GI)-selective calcium channel antagonist, inhibits the influx of calcium into intestinal smooth muscle cells, thus relieving the contraction of intestinal smooth muscles, defecation-associated abdominal pain, and discomfort in patients with irritable bowel syndrome (IBS) . In recent years, pinaverium bromide was found to attenuate lipopolysaccharide (LPS)-induced excessive systemic inflammation via inhibiting neutrophil priming and protected the liver and lung from LPS-induced damage and reduced organ-specific inflammatory responses . However, there is no report on the antibacterial activity of pinaverium bromide, either for Gram-positive or Gram-negative bacteria.…”

“…14 In recent years, pinaverium bromide was found to attenuate lipopolysaccharide (LPS)-induced excessive systemic inflammation via inhibiting neutrophil priming and protected the liver and lung from LPS-induced damage and reduced organ-specific inflammatory responses. 15 However, there is no report on the antibacterial activity of pinaverium bromide, either for Grampositive or Gram-negative bacteria. This study first found that pinaverium bromide had antibacterial activity against S. aureus and E. faecalis.…”