Pharmacologic Inhibition of COX-1 and COX-2 in Influenza A Viral Infection in Mice

PLoS One. 2010 Jul 15;5(7):e11610. doi: 10.1371/journal.pone.0011610.

Abstract

Background: We previously demonstrated that cyclooxygenase (COX)-1 deficiency results in greater morbidity and inflammation, whereas COX-2 deficiency leads to reduced morbidity, inflammation and mortality in influenza infected mice.

Methodology/principal findings: We investigated the effects of COX-1 and COX-2 inhibitors in influenza A viral infection. Mice were given a COX-1 inhibitor (SC-560), a COX-2 inhibitor (celecoxib) or no inhibitor beginning 2 weeks prior to influenza A viral infection (200 PFU) and throughout the course of the experiment. Body weight and temperature were measured daily as indicators of morbidity. Animals were sacrificed on days 1 and 4 post-infection and bronchoalveolar lavage (BAL) fluid was collected or daily mortality was recorded up to 2 weeks post-infection. Treatment with SC-560 significantly increased mortality and was associated with profound hypothermia and greater weight loss compared to celecoxib or control groups. On day 4 of infection, BAL fluid cells were modestly elevated in celecoxib treated mice compared to SC-560 or control groups. Viral titres were similar between treatment groups. Levels of TNF-alpha and G-CSF were significantly attenuated in the SC-560 and celecoxib groups versus control and IL-6 levels were significantly lower in BAL fluid of celecoxib treated mice versus control and versus the SC-560 group. The chemokine KC was significantly lower in SC-560 group versus control.

Conclusions/significance: Treatment with a COX-1 inhibitor during influenza A viral infection is detrimental to the host whereas inhibition of COX-2 does not significantly modulate disease severity. COX-1 plays a critical role in controlling the thermoregulatory response to influenza A viral infection in mice.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Celecoxib
  • Cyclooxygenase 1 / metabolism*
  • Cyclooxygenase 2 / metabolism*
  • Cyclooxygenase Inhibitors / therapeutic use*
  • Female
  • Influenza A virus / drug effects*
  • Influenza A virus / enzymology*
  • Influenza A virus / pathogenicity
  • Mice
  • Orthomyxoviridae Infections / drug therapy*
  • Orthomyxoviridae Infections / virology
  • Pyrazoles / therapeutic use
  • Sulfonamides / therapeutic use

Substances

  • Cyclooxygenase Inhibitors
  • Pyrazoles
  • SC 560
  • Sulfonamides
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Celecoxib