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

Abstract

BackgroundWe 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 FindingsWe 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-α 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/SignificanceTreatment 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.

Prostaglandin E2 Induction during Mouse Adenovirus Type 1 Respiratory Infection Regulates Inflammatory Mediator Generation but Does Not Affect Viral Pathogenesis

“…Decreased PGE 2 production is associated with decreased virus-induced cytokine production following influenza virus infection of COX-2 -/- mice or mice treated with the COX-2 inhibitor celecoxib [30,54]. We hypothesized that PGE 2 promotes virus-induced cytokine and chemokine production following MAV-1 infection.…”

“…For example, inhibition of PGE 2 production during influenza or RSV infection has significant effects on virus-induced inflammatory responses. During influenza infection, treatment of mice with the COX-2 inhibitor celecoxib suppresses virus-induced production of proinflammatory cytokines in the lungs, although it does not affect viral titers or disease severity [54]. Treatment of influenza-infected mice with COX inhibitors results in improved lung function and reduced immunopathology [56].…”

Targeting the “Cytokine Storm” for Therapeutic Benefit

“…Selective inhibition of COX-1 has been shown to increase mortality and disease symptoms in experimental sepsis and systemic inflammation (66). In comparison, selective COX-2 inhibitors have been shown to significantly reduce levels of inflammation, without the damaging gastrointestinal side effects.…”

Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Induces Prostaglandin E 2 Production through Cyclooxygenase 1, Which Is Dependent on the ERK1/2-p-C/EBP-β Pathway

“…However, in some cases, COX-1 can be upregulated and play a role in PGE 2 production (37). For example, COX-1 was found to promote PGE 2 production and control the thermoregulatory response to influenza A virus infection at 4 dpi in mice (38). Mice deficient in gelatinase B (matrix metallopeptidase 9 [MMP-9]) develop a compensatory mechanism involving the COX-1-PGE 2 pathway in macrophages, resulting in enhanced early vascular permeability (39).…”