Pharmacologic inhibition of COX-1 and COX-2 in influenza A viral infection in mice

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.

Figure 1. Mortality following influenza A viral infection in control (n = 30), SC-560 (n = 19) and celecoxib (n = 19) treatment groups; *p<0.05 versus control, ∧ p<0.05 versus celecoxib.

Figure 2. Time course of body temperature changes following influenza A viral infection in control, SC-560 and celecoxib treatment groups.

Numbers of mice in each group and timepoint are shown in the table. Data represent mean ± SEM; *p<0.05 versus control.

Figure 3. Time course of body weight changes following influenza A viral infection in control, SC-560 and celecoxib treatment groups.

Numbers of mice in each group and timepoint are shown in the table. Data represent mean ± SEM; *p<0.05 versus control.

Figure 4. BAL fluid cellularity on days 1 and 4 of infection in control, SC-560 and celecoxib treatment groups.

Data represent mean ± SEM (n = 16–17 per group and timepoint). *p<0.05 versus control, ∧ p<0.05 versus SC-560.

Figure 5. Lung viral titres on days 1 and 4 of infection.

Data represent mean ± SEM (n = 8–10 per group and timepoint). Differences between the three treatment groups are not statistically significant; however, viral titres on day 4 are significantly higher than on day 1 for each group.

Figure 6. Overview of study design.

(A) Inflammatory endpoints. (B) Clinical endpoints.