tetano
Editor, Senior Moderator
Br J Pharmacol. 2019 Jul 4. doi: 10.1111/bph.14787. [Epub ahead of print]
[h=1]Repurposing drugs targeting the P2X7 receptor to limit hyperinflammation and disease during influenza virus infection.[/h] Rosli S[SUP]1,[/SUP][SUP]2[/SUP], Kirby FJ[SUP]1,[/SUP][SUP]2[/SUP], Lawlor KE[SUP]1,[/SUP][SUP]2[/SUP], Rainczuk K[SUP]1,[/SUP][SUP]2[/SUP], Drummond GR[SUP]3[/SUP], Mansell A[SUP]1,[/SUP][SUP]2[/SUP], Tate MD[SUP]1,[/SUP][SUP]2[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] [h=4]BACKGROUND AND PURPOSE:[/h] Severe influenza A virus (IAV) infections are associated with damaging hyperinflammation that can lead to mortality. There is an urgent need to identify new therapeutics to treat severe and pathogenic IAV infections. The repurposing of drugs with an existing and studied pharmacokinetic and safety profile is a highly attractive potential strategy. We have previously demonstrated that the NLRP3 inflammasome plays a temporal role during severe IAV infection with early protective responses, however, subsequent dysregulation leads to excessive inflammation, contributing to disease severity.
[h=4]EXPERIMENTAL APPROACH:[/h] We evaluated the use of existing drugs to target P2X7 receptor signalling and dampen NLRP3 inflammasome responses during severe IAV infection. The ability of Probenecid and AZ11645373 to limit NLRP3 inflammasome-dependent IL-1β secretion in vitro was evaluated. The effectiveness of Probenecid and AZ11645373 treatment at reducing hyperinflammation and disease during severe IAV infection was demonstrated.
[h=4]KEY RESULTS:[/h] Probenecid and AZ11645373 treatment of macrophages in vitro diminished NLRP3 inflammasome-dependent IL-1β secretion. Intranasal therapeutic treatment of mice displaying severe influenza disease with Probenecid or AZ11645373 reduced pro-inflammatory cytokine production, cellular infiltrates in the lung and provided protection against disease. Importantly, Probenecid and AZ11645737 could be administered at either early or late stage of disease and provide therapeutic efficacy.
[h=4]CONCLUSIONS AND IMPLICATIONS:[/h] Our study demonstrates that the anti-inflammatory drugs Probenecid and AZ11645373, which have documented pharmacokinetics and safety profiles in humans, are effective at dampening hyperinflammation and severe influenza disease providing potentially new therapeutic strategies for treating severe or pathogenic IAV infections.
This article is protected by copyright. All rights reserved.
PMID: 31271646 DOI: 10.1111/bph.14787
[h=1]Repurposing drugs targeting the P2X7 receptor to limit hyperinflammation and disease during influenza virus infection.[/h] Rosli S[SUP]1,[/SUP][SUP]2[/SUP], Kirby FJ[SUP]1,[/SUP][SUP]2[/SUP], Lawlor KE[SUP]1,[/SUP][SUP]2[/SUP], Rainczuk K[SUP]1,[/SUP][SUP]2[/SUP], Drummond GR[SUP]3[/SUP], Mansell A[SUP]1,[/SUP][SUP]2[/SUP], Tate MD[SUP]1,[/SUP][SUP]2[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] [h=4]BACKGROUND AND PURPOSE:[/h] Severe influenza A virus (IAV) infections are associated with damaging hyperinflammation that can lead to mortality. There is an urgent need to identify new therapeutics to treat severe and pathogenic IAV infections. The repurposing of drugs with an existing and studied pharmacokinetic and safety profile is a highly attractive potential strategy. We have previously demonstrated that the NLRP3 inflammasome plays a temporal role during severe IAV infection with early protective responses, however, subsequent dysregulation leads to excessive inflammation, contributing to disease severity.
[h=4]EXPERIMENTAL APPROACH:[/h] We evaluated the use of existing drugs to target P2X7 receptor signalling and dampen NLRP3 inflammasome responses during severe IAV infection. The ability of Probenecid and AZ11645373 to limit NLRP3 inflammasome-dependent IL-1β secretion in vitro was evaluated. The effectiveness of Probenecid and AZ11645373 treatment at reducing hyperinflammation and disease during severe IAV infection was demonstrated.
[h=4]KEY RESULTS:[/h] Probenecid and AZ11645373 treatment of macrophages in vitro diminished NLRP3 inflammasome-dependent IL-1β secretion. Intranasal therapeutic treatment of mice displaying severe influenza disease with Probenecid or AZ11645373 reduced pro-inflammatory cytokine production, cellular infiltrates in the lung and provided protection against disease. Importantly, Probenecid and AZ11645737 could be administered at either early or late stage of disease and provide therapeutic efficacy.
[h=4]CONCLUSIONS AND IMPLICATIONS:[/h] Our study demonstrates that the anti-inflammatory drugs Probenecid and AZ11645373, which have documented pharmacokinetics and safety profiles in humans, are effective at dampening hyperinflammation and severe influenza disease providing potentially new therapeutic strategies for treating severe or pathogenic IAV infections.
This article is protected by copyright. All rights reserved.
PMID: 31271646 DOI: 10.1111/bph.14787