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A cytokine storm is one of the leading causes of acute respiratory distress syndrome (ARDS) and sepsis‐associated multiple organ failure in many respiratory viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). The coronavirus disease 2019 (COVID‐19) pandemic has caused millions of deaths worldwide, resulting in an urgent need for effective therapeutic interventions. Repurposing immunosuppressive drugs that target cytokines with immunomodulatory properties is a promising approach to counteract SARS‐CoV‐2‐induced ARDS at the infective and post‐infective stages. In this minireview, we examine drugs targeting IL‐1β, IL‐4/IL‐13, IL‐6 and TNF‐α tested in COVID‐19 patients. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a major global public health problem. Infection by this virus involves many pathophysiological processes, such as a "cytokine storm," that is, very aggressive inflammatory response that offers new perspectives for the management and treatment of patients. Here, we analyse relevant mechanism involved in the hyperthermia‐mediated heat shock factors (HSFs)/heat shock proteins (HSP)70 pathway which may provide a possible treatment tool. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID‐19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc [ABSTRACT FROM AUTHOR]

Identifying drug targets mitigating vascular dysfunction, thrombo‐inflammation and thromboembolic complications in COVID‐19 is essential. COVID‐19 coagulopathy differs from sepsis coagulopathy. Factors that drive severe lung pathology and coagulation abnormalities in COVID‐19 are not understood. Protein–protein interaction studies indicate that the tagged viral bait protein ORF9c directly interacts with PAR2, which modulates host cell IFN and inflammatory cytokines. In addition to direct interaction of SARS‐CoV‐2 viral protein with PARs, we speculate that activation of PAR by proteases plays a role in COVID‐19‐induced hyperinflammation. In COVID‐19‐associated coagulopathy elevated levels of activated coagulation proteases may cleave PARs in association with TMPRSS2. PARs activation enhances the release of cytokines, chemokines and tissue factor expression to propagate IFN‐dependent inflammation, leukocyte‐endothelial interaction, vascular permeability and coagulation responses. This hypothesis, corroborated by in vitro findings and emerging clinical evidence, will focus targeted studies of PAR1/2 blockers as adjuvant drugs against cytokine release syndrome and COVID‐19‐associated coagulopathy. LINKED ARTICLES: This article is part of a themed issue on The second wave: are we any closer to efficacious pharmacotherapy for COVID 19? (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.10/issuetoc [ABSTRACT FROM AUTHOR]

Background and Purpose: Staphylococcal enterotoxin‐B (SEB) is one of the most potent bacterial superantigens that exerts profound toxic effects by inducing a cytokine storm. Inhaled SEB can cause acute respiratory distress syndrome (ARDS), which is often fatal and with no effective treatments. Experimental Approach Efficacy of Δ9‐tetrahydrocannabinol (THC) was tested in a mouse model of SEB‐mediated ARDS, in which lung inflammation, alterations in gut/lung microbiota and production of short‐chain fatty acids (SCFAs) was measured. Gene dysregulation of lung epithelial cells was studied by transcriptome arrays. Faecal microbiota transplantation (FMT) was performed to confirm the role of microbiota in suppressing ARDS. Key Results: While SEB triggered ARDS and 100% mortality in mice, THC protected the mice from fatality. Pyrosequencing analysis revealed that THC caused significant and similar alterations in microbiota in the lungs and gut of mice exposed to SEB. THC significantly increased the abundance of beneficial bacterial species, Ruminococcus gnavus, but decreased pathogenic microbiota, Akkermansia muciniphila. FMT confirmed that THC‐mediated reversal of microbial dysbiosis played crucial role in attenuation of SEB‐mediated ARDS. THC treatment caused an increase in SCFA, of which propionic acid was found to inhibit the inflammatory response. Transcriptome array showed that THC up‐regulated several genes like lysozyme1 and lysozyme2, β‐defensin‐2, claudin, zonula‐1, occludin‐1, Mucin2 and Muc5b while down‐regulating β‐defensin‐1. Conclusion and Implications: The study demonstrates for the first time that THC attenuates SEB‐mediated ARDS and toxicity by altering the microbiota in the lungs and the gut as well as promoting antimicrobial and anti‐inflammatory pathways. [ABSTRACT FROM AUTHOR]

The COVID‐19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has overwhelmed healthcare systems requiring the rapid development of treatments, at least, to reduce COVID‐19 severity. Drug repurposing offers a fast track. Here, we discuss the potential beneficial effects of statins in COVID‐19 patients based on evidence that they may target virus receptors, replication, degradation, and downstream responses in infected cells, addressing both basic research and epidemiological information. Briefly, statins could modulate virus entry, acting on the SARS‐CoV‐2 receptors, ACE2 and CD147, and/or lipid rafts engagement. Statins, by inducing autophagy activation, could regulate virus replication or degradation, exerting protective effects. The well‐known anti‐inflammatory properties of statins, by blocking several molecular mechanisms, including NF‐κB and NLRP3 inflammasomes, could limit the "cytokine storm" in severe COVID‐19 patients which is linked to fatal outcome. Finally, statin moderation of coagulation response activation may also contribute to improving COVID‐19 outcomes. Linked Articles: This article is part of a themed issue on The Pharmacology of COVID‐19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID‐19), the disease resulting from infection by a novel coronavirus, SARS‐Cov2, has rapidly spread since November 2019 leading to a global pandemic. SARS‐Cov2 has infected over four million people and caused over 290,000 deaths worldwide. Although most cases are mild, a subset of patients develop a severe and atypical presentation of acute respiratory distress syndrome (ARDS) that is characterised by a cytokine release storm (CRS). Paradoxically, treatment with anti‐inflammatory agents and immune regulators has been associated with worsening of ARDS. We hypothesize that the intrinsic circadian clock of the lung and the immune system may regulate individual components of CRS, and thus, chronotherapy may be used to effectively manage ARDS in COVID‐19 patients. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID‐19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc [ABSTRACT FROM AUTHOR]

Severe pneumonia which shares several of the features of acute respiratory distress syndrome (ARDS) is the main cause of morbidity and mortality in Coronavirus disease 19 (Covid‐19) for which there is no effective treatment, so far. ARDS is caused and sustained by an uncontrolled inflammatory activation characterized by a massive release of cytokines (cytokine storm), diffuse lung oedema, inflammatory cell infiltration, and disseminated coagulation. Macrophage and T lymphocyte dysfunction plays a central role in this syndrome. In several experimental in vitro and in vivo models, many of these pathophysiological changes are triggered by stimulation of the P2X7 receptor. We hypothesize that this receptor might be an ideal candidate to target in Covid‐19‐associated severe pneumonia. Linked Articles: This article is part of a themed issue on The Pharmacology of COVID‐19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc [ABSTRACT FROM AUTHOR]