key: cord-1036037-sgzlzc5t authors: Salles, Évila Lopes; Khodadadi, Hesam; Jarrahi, Abbas; Ahluwalia, Meenakshi; Paffaro, Valdemar Antonio; Costigliola, Vincenzo; Yu, Jack C.; Hess, David C.; Dhandapani, Krishnan M.; Baban, Babak title: Cannabidiol (CBD) modulation of apelin in acute respiratory distress syndrome date: 2020-10-15 journal: J Cell Mol Med DOI: 10.1111/jcmm.15883 sha: 1383773d9efc47cf00b9b4bf7c7a5ad4e11e1ddf doc_id: 1036037 cord_uid: sgzlzc5t Considering lack of target‐specific antiviral treatment and vaccination for COVID‐19, it is absolutely exigent to have an effective therapeutic modality to reduce hospitalization and mortality rate as well as to improve COVID‐19‐infected patient outcomes. In a follow‐up study to our recent findings indicating the potential of Cannabidiol (CBD) in the treatment of acute respiratory distress syndrome (ARDS), here we show for the first time that CBD may ameliorate the symptoms of ARDS through up‐regulation of apelin, a peptide with significant role in the central and peripheral regulation of immunity, CNS, metabolic and cardiovascular system. By administering intranasal Poly (I:C), a synthetic viral dsRNA, while we were able to mimic the symptoms of ARDS in a murine model, interestingly, there was a significant decrease in the expression of apelin in both blood and lung tissues. CBD treatment was able to reverse the symptoms of ARDS towards a normal level. Importantly, CBD treatment increased the apelin expression significantly, suggesting a potential crosstalk between apelinergic system and CBD may be the therapeutic target in the treatment of inflammatory diseases such as COVID‐19 and many other pathologic conditions. COVID-19 pandemic has profoundly affected human life, inducing high patient morbidity and mortality while stressing health care systems worldwide. SARS-CoV-2, the highly infectious agent responsible for the COVID-19 pandemic, is a novel coronavirus that utilizes a glycosylated spike protein to enter human cells via the angiotensin-converting enzyme 2 (ACE2) receptor. The lung is a primary site of entry for SARS-CoV-2, as evidenced by massive pulmonary inflammation and development of acute respiratory distress syndrome (ARDS). 1 These changes frequently result in a cytokine storm that contributes to diffuse alveolar damage, alveolar capillary leakage, severe hypoxaemia, intense pulmonary oedema and pulmonary fibrosis. (IL-1β), IL-6, tumour necrosis factor-α (TNF-α), chemokine (CC-motif) ligand 2 (CCL2), chemokine (CC-motif) ligand 3 (CCL3)), this issue remains largely unresolved and, once elucidated, may identify novel approaches to improve outcomes in COVID-19-infected patients. 5 Apelin, an endogenous, multi-functional ligand for the G protein-coupled receptor, APJ, also serves as a second catalytic substrate for ACE2. 6 Apelin is generated from a 77-amino acid precursor and undergoes proteolytic cleavage to generate biological active fragments, including apelin-36, apelin-19 and apelin-13. An endogenous protective role was postulated for activation of the apelin/APJ axis (Apelinergic system) after lung injury, via proposed mechanisms including suppression of the immune activating transcription factor, NF-κB and inhibition of innate immune infiltration/activation via attenuated expression of CCL2, CCL3, CCL4, CCL7 and TNF-α. 7 Of interest, both apelin and APJ are widely expressed throughout the lung, heart, liver, gut, kidney and central nervous system, 8 spatially overlapping expression of the endocannabinoid system while interaction between the endocannabinoid system and apelin limits liver fibrosis. 9 Based on these studies, we suggested that regulation of the apelinergic system by CBD may limit excessive pulmonary inflammation after experimental ARDS. Immunofluorescence analysis of lung tissue revealed a reduction in apelin immunoreactivity after poly I:C treatment, as compared to control mice (Figure 2) . Importantly, treatment with CBD increased F I G U R E 2 CBD improved the symptoms of Poly(I:C)-induced ARDS and normalized the apelin expression in the lung tissues. Masson's trichrome analysis of lung tissues showed that intranasal administration of high dose Poly(I:C) caused the destruction of normal morphology and structure of lung, hypertrophy, fibrosis and pulmonary oedema, as compared to the tissues from control group. CBD treatment improved the structure towards the normal architecture (bright filed images on the left panel). Further, immunofluorescence analysis of lung tissue (panels on the right side) showed a decrease in Apelin in Poly(I:C) treated lung compared to normal tissues. CBD treatment normalized the Apelin expression in the lung, indicating the potential protective effect of CBD apelin expression towards control levels in the lung following poly I:C administration (Figure 2 ). Our data demonstrate that CBD improves lung structure and exerts a potent anti-inflammatory effect following experimental ARDS. The beneficial effects of CBD were correlated with the regulation of apelin, an endogenous peptide with protective effects in pulmonary tissue. Thus, apelin may represent a novel molecular target underlying the protective effects of endocannabinoid signalling, including regulation by CBD. Additionally, apelin may represent an unexplored biomarker for the early diagnosis of ARDS. Towards this end, apelin may have utility as a prognostic and predictive biomarker to categorize the risk of deterioration and disease progression. Of similar importance, apelin may serve a powerful and sensitive role as a pharmacodynamic biomarker, providing a biological readout to monitor the efficacy of a therapeutic intervention. Given that apelin is also a substrate for ACE2, these findings may be particularly relevant to the management of COVID-19. Future pre-clinical and clinical studies will explore these exciting possibilities. The data that support the findings of this study are available from the corresponding author (BB) upon request. https://orcid.org/0000-0002-3144-2288 Lung repair and regeneration in ARDS: Role of PECAM1 and Wnt Signaling Cannabidiol (CBD) modulates cytokine storm in Acute Respiratory Distress Syndrome induced by simulated viral infection using synthetic RNA The Potential of Cannabidiol in the COVID-19 Pandemic: A Hypothesis Letter Immune Responses Regulated by Cannabidiol The ACE2/apelin signaling, microRNAs, and hypertension The apelin-APJ axis: A novel potential therapeutic target for organ fibrosis Molecular properties of apelin: Tissue distribution and receptor binding Roles of the Hepatic Endocannabinoid and Apelin Systems in the Pathogenesis of Liver Fibrosis Long-term activation of TLR3 by poly(I:C) induces inflammation and impairs lung function in mice