In-vitro anti-inflammatory and immunomodulatory effects of grepafloxacin in zymogen A- or Staphylococcus aureus-stimulated human THP-1 monocytes.
The effects of grepafloxacin on the release of cytokines, chemical mediators, hydrolytic enzyme activities, and lipoxygenation in zymogen A- or Staphylococcus aureus-stimulated human THP-1 monocytes were evaluated. Initially, consistent with stimulation of phagocytic mechanisms of the monocytes, increases in cyclic adenosine monophosphate (cAMP) release, nitric oxide [NO] release, and hydrogen peroxide [H(2)O(2)] release, with a small decrease in cellular pH, occurred within 2 h. Enzymatic activities associated with oxygen burst of phagocytic cells (e.g., protein kinase C and nicotinamide adenine dinucleotide phosphate, reduced (NADPH) oxidase) were elevated, suggesting that monocytes attempted to destroy the invading organism through an innate phagocytic cidal immunologic mechanism. After 1-2 h of exposure to grepafloxacin, the oxygen burst and the release of proinflammatory cytokines and chemical mediators were suppressed. After 4 h, suppression of n-acetyl glucosaminidase (NAG) and cathepsin D activities and lipid peroxidation occurred, suppressing the pathogen-induced spread of infection and inflammation. Release of tumor necrosis factor (TNFalpha), interleukin (IL)-1, IL-6, and IL-8 was inhibited by grepafloxacin in a concentration-dependent manner, suggesting a reduction in the acute-phase inflammatory responses initiated by cytokine release from monocytes. Later, S. aureus were killed through inhibition of DNA synthesis, consistent with a bacteriostatic effect. Drug action against invading organisms appears to occur through multiple processes. Modulation of the innate immune system occurs within the first hour, causing the activation of cytokines, chemical mediators, and hydrolytic enzymes. A second phase between 2-4 h appears to involve the suppression of cellular components involved in inflammation and the spread of the infection. The third response, an apparent bacteriostatic inhibition of DNA synthesis, causes bacterial death.
Ives
Timothy J
TJ
Division of Pharmacotherapy, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 257599-7360, USA. tjives@med.unc.edu
Schwab
Ute E
UE
Ward
E Stacy
ES
Hall
Iris H
IH
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004792:Enzyme Precursors / Q000494:pharmacology*; D024841:Fluoroquinolones; D006801:Humans; D009000:Monocytes / Q000187:drug effects*; D010587:Phagocytosis / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000276:immunology; D013482:Superoxide Dismutase / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D000890:Anti-Infective Agents; D000893:Anti-Inflammatory Agents; D004792:Enzyme Precursors; D024841:Fluoroquinolones; D010879:Piperazines; D013482:Superoxide Dismutase; C075375:grepafloxacin