key: cord-0796291-hh5iov17 authors: Christman, John W; Karpurapu, Manjula; Pei, Dehua title: Can acute respiratory distress syndrome be treated? date: 2021-03-16 journal: Future medicinal chemistry DOI: 10.4155/fmc-2021-0014 sha: b7541dfb5bd57d2f771ca2c595e4ad66b69ccc6a doc_id: 796291 cord_uid: hh5iov17 nan complement cascade, which further intensifies lung and systemic inflammation. Thus, induction of cytokine storm resulting in damage to the alveolar capillary barrier and dysregulation of innate immunity is believed to be the primary driver of the pathogenesis of ARDS. Effective management of ARDS patients ideally involves a multidisciplinary team that includes a critical care physician, a critical care nurse, a respiratory therapist, a dietician, physical and occupational therapists, and a PharmD. Treatment for ARDS is focused on supporting oxygenation and ventilation without inflicting ventilator induced lung injury [5] . This is accomplished by ventilation with positive end expiratory pressure, which prevents lung injury induced by opening and closing of distal alveoli, referred to as atelectrauma. Ventilation using small tidal volumes (6 ml/kg ideal body weight) prevents volutrauma (i.e., overexpansion and damage of any remaining relatively normal alveoli). Positive pressure ventilation aims to keep the distending inspiratory pressure below 30 cm of water to prevent barotrauma. Finally, alternating patient positioning from supine to prone improve survival by resulting in a beneficial gravitational impact on lung infiltrates that minimizes regional physical forces and limits lung injury while improving oxygenation [6] . In extreme situations, ARDS patients are supported by extracorporeal membrane oxygenation [7] . Other effective management strategies include aggressive treatment of hypotension (shock) with fluids and vasopressors, avoidance of salt and water overload with diuretics and hemofiltration, and treatment of multiple organ failure with measures such as hemodialysis and transfusion of blood products. Additional helpful measures include the daily use of a checklist to ensure antibiotic stewardship, optimal use of sedation, prevention of deep venous thrombosis and pulmonary embolism, and nutritional support. Finally, physical and occupational therapy with early ambulation is beneficial for patients in the early recovery stages of ARDS. There are no pharmacologic agents that specifically treat the underlying molecular pathophysiology of ARDS, although several drugs are widely used as supportive measures. For example, severely hypoxemic patients may be therapeutically paralyzed with neuromuscular blockers in combination with deep sedation to prevent ventilator dyssynchrony. Vasopressin and corticosteroids may be helpful adjunctive treatments for circulatory collapse, and broad-spectrum antibiotics are often necessary for treating any suspected or proven bacterial infections. Since the first report of ARDS almost 50 years ago [8] , many pharmacologic agents have been evaluated for treating ARDS. To date, a few have shown promise in animal models and early stages of clinical investigations, but none have been effective in phase III randomized clinical trials (RCTs); these include β2 adrenergic agonist therapy [9] , early neuromuscular blockade [10] , omega-3 fatty acids [11] , rosuvastatin [12] and vitamin D [13] . The only agent that has shown clear clinical benefits is dexamethasone. In a randomized trial of 277 moderate to severe ARDS patients, treatment with dexamethasone showed an improvement in survival in the treatment group as compared with the placebo group over 60 days [14] . In another randomized trial of 299 COVID-19 patients with ARDS, dexamethasone increased the number of ventilator-free days over 28 days [15] . However, there is some concern that the prolonged use of high dosages of steroids can results in neuromuscular disability in some patients. Vitamin C represents another promising but as yet inconclusive agent for treatment of ARDS. In a randomized trial of 167 patients with severe sepsis and acute respiratory failure, treatment with high doses of vitamin C failed to show significant improvement in the primary outcomes compared with the placebo group; however, a significant difference in the secondary outcomes was observed, including the 28-day mortality rate and the number of ventilator-and hospital-free days [16] . Similarly, treatment with allogeneic mesenchymal stromal cells in a small RCT of 60 patients with moderate to severe ARDS demonstrated safety but was inconclusive with respect to efficacy because of an unexpected cell viability issue [17] . In an early Phase 1 clinical trial of sepsis-induced ARDS, low-dose carbon monoxide was not associated with adverse events, but the study was not sufficiently powered for efficacy. Angiotensin-converting enzyme inhibitors SARS-CoV-2 gains entry to lung cells through a mechanism that involves angiotensin-converting enzyme 2. Viral entry and multiplication are believed to disrupt the integrity of the alveolar capillary barrier leading to an increase in vascular permeability and pulmonary edema. An international multicenter RCT that examines the efficacy of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in COVID19 ARDS has been initiated, but results have not yet been reported [18] . In an RCT of 243 hospitalized, moderately ill COVID19 patients with ARDS, treatment with tocilizumab showed no difference in preventing tracheal intubation or death, nor any difference in oxygenation at 5 or 14 days [19] . Although not yet peer reviewed, a recent report suggested that in a larger international multicenter RCT, tocilizumab or sarilumab resulted in a modest survival benefit. We and others have shown that depletion of macrophages by treatment with clodronate suppresses endotoxininduced neutrophilic inflammation in mouse lungs. We further showed that upon treatment with lipopolysaccharides, activated NFATc3 regulates the expression of CCR2 and TNF-α in macrophages and Claudin-5 in pulmonary microvascular endothelial cells. These results suggested that pharmacologic inhibition of the NFATc3 function could provide an effective therapy for ARDS. We have recently developed a selective peptidyl inhibitor of the calcineurin-NFAT interaction, CNI103. CNI103 blocked NFATc3 activation in lung macrophages, decreased the production of TNF-α and IL-6, and prevented the development of sepsis-induced acute lung injury/ARDS in a mouse model [20] . In vitro/ex vivo studies demonstrate that CNI103 readily enters macrophages, monocytes and neutrophils but less efficiently T or B cells, suggesting that CNI103 may attenuate the inflammatory responses to viral infection without blocking T-and B-cell-mediated viral clearance. Our initial investigations indicate that CNI103 is well tolerated with limited, if any, toxicity. We are hopeful that CNI103 or a derivative will be tested in a future RCT. ARDS is a common and highly lethal condition. The mortality has improved with supportive care over the past few decades, but the morbidity has not. Although there is no current treatment for ARDS that is based on molecular mechanisms, the science of ARDS is improving rapidly. The current pandemic has emphasized the urgent need for treatments that reduce the mortality and alleviate the morbidity of ARDS. The authors are co-inventors of a patent application filed on calcineurin inhibitors including CNI103. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. 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