Early alveolar epithelial cell necrosis is a potential driver of COVID-19-induced acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) with COVID-19 is aggravated by hyperinflammatory responses even after the peak of the viral load has passed; however, its underlying mechanisms remain unclear. In the present study, analysis of the alveolar tissue injury markers and epithelial cell death markers in patients with COVID-19 revealed that COVID-19-induced ARDS was characterized by alveolar epithelial necrosis at an early disease stage. Serum levels of HMGB-1, one of the DAMPs released from necrotic cells, were also significantly elevated in these patients. Further analysis using a mouse model mimicking COVID-19-induced ARDS showed that the alveolar epithelial cell necrosis involved two forms of programmed necrosis, namely necroptosis, and pyroptosis. Finally, the neutralization of HMGB-1 attenuated alveolar tissue injury in the mouse model. Collectively, necrosis, including necroptosis and pyroptosis, is the predominant form of alveolar epithelial cell death at an early disease stage and subsequent release of DAMPs is a potential driver of COVID-19-induced ARDS.

Necrosis Rather Than Apoptosis is the Dominant form of Alveolar Epithelial Cell Death in Lipopolysaccharide-Induced Experimental Acute Respiratory Distress Syndrome Model.

Alveolar epithelial cell (AEC) death, which is classified as apoptosis or necrosis, plays a critical role in the pathogenesis of acute respiratory distress syndrome (ARDS). In addition to apoptosis, some types of necrosis are known to be molecularly regulated, and both apoptosis and necrosis can be therapeutic targets for diseases. However, the relative contribution of apoptosis and necrosis to AEC death during ARDS has not been elucidated. Here, we evaluated which type of AEC death is dominant and whether regulated necrosis is involved in lipopolysaccharide (LPS)-induced lung injury, an experimental ARDS model. In the bronchoalveolar lavage fluid from the LPS-induced lung injury mice, both the levels of cytokeratin 18-M65 antigen (a marker of total epithelial cell death) and cytokeratin 18-M30 antigen (an epithelial apoptosis marker) were increased. The M30/M65 ratio, which is an indicator of the proportion of apoptosis to total epithelial cell death, was significantly lower than that in healthy controls. In addition, the number of propidium iodide-positive, membrane-disrupted cells was significantly higher than the number of TUNEL-positive apoptotic cells in the lung sections of lung injury mice. Activated neutrophils seemed to mediate AEC death. Finally, we demonstrated that necroptosis, a regulated necrosis pathway, is involved in AEC death during LPS-induced lung injury. These results indicate that necrosis including necroptosis, rather than apoptosis, is the dominant type of AEC death in LPS-induced lung injury. Although further studies investigating human ARDS subjects are necessary, targeting necrosis including its regulated forms might represent a more efficient approach to protecting the alveolar epithelial barrier during ARDS.

Enhancement of glycolysis by inhibition of oxygen-sensing prolyl hydroxylases protects alveolar epithelial cells from acute lung injury.

Cellular bioenergetic failure caused by mitochondrial dysfunction is a key process of alveolar epithelial injury during acute respiratory distress syndrome (ARDS). Prolyl hydroxylases (PHDs) act as cellular oxygen sensors, and their inhibition activates hypoxia-inducible factor (HIF), resulting in enhanced cellular glycolytic activity, which could compensate for impaired mitochondrial function and protect alveolar epithelial cells from ARDS. Here, we evaluated the effects of pharmacological PHD inhibition with dimethyloxalylglycine (DMOG) on alveolar epithelial cell injury using in vitro and in vivo ARDS models. We established an in vitro model of alveolar epithelial injury mimicking ARDS by adding isolated neutrophils and LPS to cultured MLE12 alveolar epithelial cells. DMOG treatment protected MLE12 cells from neutrophil-LPS-induced ATP decline and cell death. Knockdown of HIF-1α or inhibition of glycolysis abolished the protective effect of DMOG, suggesting that it was exerted by HIF-1-dependent enhancement of glycolysis. Additionally, intratracheal DMOG administration to mice protected the alveolar epithelial barrier and improved arterial oxygenation, preventing ATP decline during LPS-induced lung injury. In summary, enhancement of glycolysis by PHD inhibition is a potential therapeutic approach for ARDS, protecting alveolar epithelial cells from bioenergetic failure and cell death.- Tojo, K., Tamada, N., Nagamine, Y., Yazawa, T., Ota, S., Goto, T. Enhancement of glycolysis by inhibition of oxygen-sensing prolyl hydroxylases protects alveolar epithelial cells from acute lung injury. FASEB J. 32, 2258-2268 (2018). www.fasebj.org.

Independent risk factors for a complicated hospital course in intensive care unit overdose patients.

Aim: The purpose of the present study was to identify risk factors associated with a complicated hospital course in overdose patients admitted to the intensive care unit. Methods: A total of 335 overdose patients were retrospectively studied in the surgical and medical intensive care unit of an academic tertiary hospital. Factors possibly associated with a complicated hospital course were evaluated. Complicated hospital course was defined as the occurrence of pneumonia, rhabdomyolysis, decubitus ulcer, nerve palsy, prolonged intubation, prolonged hospitalization, or death. Results: Of the 335 overdose patients, 93 (27.8%) had a complicated hospital course. Complicated hospital course was found to be associated with a high number of ingested pills (median, 135 [interquartile range, 78-240] versus 84 [53-134] tablets, P < 0.0001), low Glasgow Coma Scale score on admission (7 [3-11] versus 13 [8-15], P < 0.0001), and a high serum lactate level on admission (1.8 [1.0-3.0] versus 1.4 [0.9-2.0] mg/dL, P < 0.01) on univariate analysis of these factors in patients with and without a complicated hospital course. The independent risk factors for a complicated hospital course identified on multivariate analysis were a high number of ingested pills (≥100 tablets), low admission Glasgow Coma Scale score (<9), and high serum lactate on admission (≥2.0 mg/dL). The probability of a complicated hospital course for patients with 0, 1, 2, or all 3 independent risk factors were 7%, 22%, 40%, and 81%, respectively. Conclusion: The total number of ingested pills, admission Glasgow Coma Scale score, and serum lactate level on admission are predictive of a complicated hospital course in overdose patients admitted to the intensive care unit.

[Use of dexmedetomidine in a critically ill patient with hyperactive delirium: a case report].

A 28-year-old male after a traffic accident was hospitalized with the abdominal pain. The abdominal CT showed deep hepatic injury. We immediately performed emergency transcatheter arterial embolization (TAE) and observed him in the ICU. His condition was stable for a while, but soon he became disoriented and restless. We diagnosed him with hyperactive delirium in the ICU and administered flunitrazepam and haloperidol but with no effect. Next, we used dexmedetomidine hydrochloride (DEX), which was effective on delirium. DEX is a potent and highly selective alpha2 adrenoreceptor agonist and has minimal respiratory depression in contrast to other sedatives. During sedation with DEX, it is easy to arouse patients with physiological stimulus. Both memory and cognition are reported to be maintained to a certain degree during sedation with DEX. Postoperative delirium has been reported to be less with DEX compared to other sedatives. Recent studies have revealed that delirium is one of the most frequent complications and an independent risk factor for prognosis in the ICU patients. DEX may be effective for controlling delirium and provide sufficient sedation without respiratory adverse effects in patients in the ICU.

[Case of thyroid crisis with persistent tachycardia diagnosed postoperatively].

A 35-year-old man with multiple bone fractures underwent an emergency operation. On arriving at the operating room, his heart rate was 160 beats x min(-1), and blood pressure was 100/50 mmHg. We anesthetized him with oxygen, sevoflurane, fentanyl and remifentanil. We suspected hypovolemia, and treated him with crystalloid and transfused red cells and fresh frozen plasma so that heart rate and blood pressure could be stabilized. Tachycardia of 140 beats x min(-1) persisted, and landiolol was continuously administered at a rate of 5-10 mg x hr(-1) after a 2.5 mg bolus injection. Heart rate became controlled around 120 beats x min(-1) without hypotension during anesthesia. Finally, we noticed thyroid crisis in this case, and diagnosed it with laboratory data after operation. We should be aware that atypical tachycardia is caused by thyroid crisis.

Synthesis of BC-ring model of globostellatic acid X methyl ester, an anti-angiogenic substance from marine sponge.

Concise synthesis of BC-ring model compounds of 13E,17E-globostellatic acid X methyl ester, an anti-angiogenic triterpene derivative from Indonesian marine sponge, was achieved through ynolate olefination and allylic oxidation as key steps. The model compound 5, which was synthesized within 10 reaction steps from commercially available Hajos-Parrish ketone, showed anti-proliferative activity against HUVECs with moderate selectivity.