Potential reversal of pulmonary vasoplegia by inhaled ibuprofenate in COVID‐19 pneumonia

Blocking the action of NLRP3 inflammasome by inhaled ibuprofenate on pulmonary macrophages infected by SARS‐CoV‐2

“…We will highlight the potential therapeutic effects of NaIHS on the NLRP3 inflammasome, providing details of all these actions in each case by cyclooxygenase 2 (COX2)‐dependent effect inhibition, 5–8,10 with the exception of caspases, which are COX‐independent effect inhibition, 9 (see Figures 1 and 2 and Table 1): It might block NLRP3 inflammasome action through the following effects: In vitro and in vivo, ibuprofen inhibits the activation of NLRP3 inflammasome 6 and thus significantly reduces the levels of caspase‐1, 6 IL‐1β 6 and IL‐18 6 . It might inhibit NLRP3 inflammasome due to its peroxisome proliferator‐activated receptor‐gamma (PPAR‐γ) agonist effect, 4,7 and it also might inhibit NLRP3 inflammasome via inhibition of membrane volume anion chloride channel and thus chloride efflux 4,8 …”

“…It may revert hypoxaemia, exclusively of the vasoplegic type 10 and thus, it might prevent NLRP3 inflammasome activation.…”

“…It might prevent pyroptosis through negative modulation of the inflammatory signalling pathway phosphoinositide 3‐kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR), 4,7 caspase‐1 4,6 , caspase‐4 4,9 and caspase‐5 4,9 . It might negatively modulate the activation and recruitment of pulmonary macrophages 6 It would negatively modulate the main inflammatory signalling pathways: COX2 5 , NF‐κB, 5 signal transducer and activator of transcription 3 (STAT3), 5 TLR4 5 and PI3K/AKT/mTOR 7 . It would negatively modulate the main pro‐inflammatory cytokines: IL‐1β, 5 tumor necrosis factor‐alpha (TNF‐α), 5 IL‐6 5 , IFN‐γ, 5 transforming growth factor‐beta 1 (TGF‐β1), 5 intercellular adhesion molecule‐1 (ICAM‐1) 5 and IL‐18 6 . It may revert hypoxaemia, exclusively of the vasoplegic type 10 and thus, it might prevent NLRP3 inflammasome activation. It would restore the RAS imbalance 5 and thus, it also might prevent NLRP3 inflammasome activation. …”

“…4 This cascade of events triggers the activation and recruitment of pulmonary macrophages, generating the cytokine storm, activation of inflammatory signalling pathways and also provoking a positive immune-inflammatory amplifying feed-back loop between all the above-mentioned components. 4 We will highlight the potential therapeutic effects of NaIHS on the NLRP3 inflammasome, providing details of all these actions in each case by cyclooxygenase 2 (COX2)dependent effect inhibition, [5][6][7][8]10 with the exception of caspases, which are COX-independent effect inhibition, 9 (see Figures 1 and 2 and Table 1):…”

“…5 By negative modulation of: COX2 5 , NF-κB 5 and TGF-β1 5 , and thus, it also might prevent the activation of NLRP3 inflammasome 6. It may revert hypoxaemia, exclusively of the vasoplegic type 10 and thus, it might prevent NLRP3 inflammasome activation. 7.…”