Therapeutic Approaches in COVID-19 Patients: The Role of the Renin-Angiotensin System.

Two and a half years after COVID-19 was first reported in China, thousands of people are still dying from the disease every day around the world. The condition is forcing physicians to adopt new treatment strategies while emphasizing continuation of vaccination programs. The renin-angiotensin system plays an important role in the development and progression of COVID-19 patients. Nonetheless, administration of recombinant angiotensin-converting enzyme 2 has been proposed for the treatment of the disease. The catalytic activity of cellular ACE2 (cACE2) and soluble ACE2 (sACE2) prevents angiotensin II and Des-Arg-bradykinin from accumulating in the body. On the other hand, SARS-CoV-2 mainly enters cells via cACE2. Thus, inhibition of ACE2 can prevent viral entry and reduce viral replication in host cells. The benefits of bradykinin inhibitors (BKs) have been reported in some COVID-19 clinical trials. Furthermore, the effects of cyclooxygenase (COX) inhibitors on ACE2 cleavage and prevention of viral entry into host cells have been reported in COVID-19 patients. However, the administration of COX inhibitors can reduce innate immune responses and have the opposite effect. A few studies suggest benefits of low-dose radiation therapy (LDR) in treating acute respiratory distress syndrome in COVID-19 patients. Nonetheless, radiation therapy can stimulate inflammatory pathways, resulting in adverse effects on lung injury in these patients. Overall, progress is being made in treating COVID-19 patients, but questions remain about which drugs will work and when. This review summarizes studies on the effects of a recombinant ACE2, BK and COX inhibitor, and LDR in patients with COVID-19.

Prognostic Value of Serial Measurement of Serum Des-Arg(9)-Bradykinin Levels in Severe COVID-19 Patients.

BACKGROUND: Excessive inflammatory immune response during SARS-CoV-2 infection contributes to severe disease in COVID-19 patients. Recently, some researchers hypothesized that dysregulation of the bradykinin (BK) system may also play a role in the pathogenesis of severe disease. Des-Arg(9)-bradykinin (DABK), an active metabolite of BK, is responsible for vasodilatation and increased permeability in the lungs and regulated by angiotensin converting enzyme 2 (ACE-2). Viral inhibition of ACE-2 by SARS-CoV-2 increases DABK levels. Serum levels of this metabolite may be linked to disease severity in COVID-19 patients. In this study, it is aimed to investigate the prognostic value of serial measurement of serum DABK levels in severe COVID-19 patients. METHODS: This prospective cohort study was conducted in hospitalized severe COVID-19 patients. Serum DABK levels of patients were serially measured on day 0, day 3 and day 5. Patients were categorized as cases with poor or good prognosis and critical or non-critical cases. Serum DABK levels of these patient groups were compared with paired sample t-test. Serum DABK levels on different days in the same patients were compared with repeated measures ANOVA tests. RESULTS: There was no statistically significant difference in serum DABK levels measured at day 0, day 3, and day 5 between good and poor prognosis groups. DABK levels in critical and non-critical COVID-19 patients also did not show any significant difference. CONCLUSIONS: According to our results serially measured serum DABK levels did not correlate with outcome of severe COVID-19 and do not have prognostic value in severe COVID-19 patients.

Potential Implications of Angiotensin-converting Enzyme 2 Blockades on Neuroinflammation in SARS-CoV-2 Infection.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) has been reported as a portal for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Consequently, scientific strategies to combat coronavirus disease of 2019 (COVID-19) were targeted to arrest SARS-CoV-2 invasion by blocking ACE2. While blocking ACE2 appears a beneficial approach to treat COVID-19, clinical concerns have been raised primarily due to the various intrinsic roles of ACE2 in neurological functions. Selective reports indicate that angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) upregulate ACE2 levels. ACE2 metabolizes angiotensin II and several peptides, including apelin-13, neurotensin, kinetensin, dynorphin, (des-Arg9) bradykinin, and (Lys-des-Arg9)-bradykinin, which may elicit neuroprotective effects. Since ARBs and ACEIs upregulate ACE2, it may be hypothesized that patients with hypertension receiving ARBs and ACEIs may have higher expression of ACE2 and thus be at a greater risk of severe disease from the SARS-CoV-2 infections. However, recent clinical reports indicate the beneficial role of ARBs/ACEIs in reducing COVID-19 severity. Together, this warrants a further study of the effects of ACE2 blockades in hypertensive patients medicated with ARBs/ACEIs, and their consequential impact on neuronal health. However, the associations between their blockade and any neuroinflammation also warrant further research. OBJECTIVE: This review collates mechanistic insights into the dichotomous roles of ACE2 in SARSCoV- 2 invasion and neurometabolic functions and the possible impact of ACE2 blockade on neuroinflammation. CONCLUSION: It has been concluded that ACE2 blockade imposes neuroinflammation.

A novel anti-inflammatory treatment for bradykinin-induced sore throat or pharyngitis.

BACKGROUND: Often thought of as a minor health concern, sore throat or pharyngitis is an important public health issue. It is one of the most common symptoms of upper respiratory diseases including COVID-19 and is a leading cause of physician visits and antibiotic prescriptions. However, few over-the-counter medications are proven to heal sore throat inflammation. METHODS: Adenocarcinomic human alveolar basal epithelial cells (A549 cells) and three dimensional organotypic human respiratory tissues were used to study inflammation and various treatment effects on respiratory epithelia. The cells and tissues were studied both in the presence and absence of bradykinin, one of the first inflammatory mediators of pharyngitis. Inflammation was measured by analyzing the levels of prostaglandin E2 (PGE2), interleukin 8 (IL-8), and leukotriene B4 (LTB4), transepithelial electrical resistance (TEER), and lactate dehydrogenase (LDH) release. Tissue morphology was analyzed by immunohistochemistry. RESULTS: In studying pharyngitis using organotypic human respiratory tissue stimulated with bradykinin, we saw an increase in PGE2 and interleukin-8 (IL-8) in response to bradykinin. Acetyl salicylic acid (ASA), a nonspecific COX inhibitor, was able to mitigate a bradykinin-induced increase in PGE2 in our studies. However, ASA was inflammatory above its therapeutic window, increasing the levels of PGE2 and IL-8 above those seen with bradykinin stimulation alone. We describe a novel, scientifically validated treatment for sore throat, that contains a low dose of ASA and other anti-inflammatory ingredients. CONCLUSION: This study elucidates the complex mechanisms involved in healing pharyngitis, an inflammatory condition of the upper respiratory epithelia. An ASA-based formula (Biovanta) mitigated bradykinin-induced inflammation more strongly than ASA alone in organotypic human respiratory tissues. Surprisingly, we found that many of the most common over the counter sore throat therapies exacerbate inflammation and IL-8 in organotypic human respiratory tissues, suggesting these common treatments may increase the likelihood of further respiratory complications.

Methylene blue may have a role in the treatment of COVID-19.

In this paper, we raise the hypothesis that Methylene Blue may be a treatment option for Corona Virus Disease of 2019 specially when combined with Non Steroid Anti-Inflammatory Drugs. In previous publications including ours, the role of kininogen system has been postulated. A correlation between clinical findings of the disease and this mechanism has been drawn to denote a pivotal role of kininogen-kallikrein system in pathophysiology of the disease. Therein the possible role of Icatibant, Ecallantide and Aprotinin in the treatment of this disease has been raised. Here we want to emphasize on an important post-receptor mechanism of bradykinin that is Nitric Oxide. We came to this aim because we found out how access to these novel treatment nominees may be expensive and unaffordable. For this reason we are focusing on possible role of an old albeit "mysterious" drug namely Methylene Blue. This medication may abort effects of Bradykinin by inhibition of Nitric Oxide synthase inhibitor and promote oxygen saturation while it is inexpensive and ubiquitously accessible. Clinical studies cannot be over emphasized.

A hypothesized role for dysregulated bradykinin signaling in COVID-19 respiratory complications.

As of April 20, 2020, over time, the COVID-19 pandemic has resulted in 157 970 deaths out of 2 319 066 confirmed cases, at a Case Fatality Rate of ~6.8%. With the pandemic rapidly spreading, and health delivery systems being overwhelmed, it is imperative that safe and effective pharmacotherapeutic strategies are rapidly explored to improve survival. In this paper, we use established and emerging evidence to propose a testable hypothesis that, a vicious positive feedback loop of des-Arg(9)-bradykinin- and bradykinin-mediated inflammation â†’ injury â†’ inflammation, likely precipitates life threatening respiratory complications in COVID-19. Through our hypothesis, we make the prediction that the FDA-approved molecule, icatibant, might be able to interrupt this feedback loop and, thereby, improve the clinical outcomes. This hypothesis could lead to basic, translational, and clinical studies aimed at reducing COVID-19 morbidity and mortality.