WWOX activates autophagy to alleviate lipopolysaccharide-induced acute lung injury by regulating mTOR.

Acute lung injury (ALI) is characterized by acute systemic inflammatory responses that may lead to severe acute respiratory distress syndrome (ARDS). The clinical course of ALI/ARDS is variable; however, it has been reported that lipopolysaccharides (LPS) play a role in its development. The fragile chromosomal site gene WWOX is highly sensitive to genotoxic stress induced by environmental exposure and is an important candidate gene for exposure-related lung disease research. However, the expression of WWOX and its role in LPS-induced ALI still remain unidentified. This study investigated the expression of WWOX in mouse lung and epithelial cells and explored the role of WWOX in LPS-induced ALI model in vitro and in vivo. In addition, we explored one of the possible mechanisms by which WWOX alleviates ALI from the perspective of autophagy. Here, we observed that LPS stimulation reduced the expression of WWOX and the autophagy marker microtubule-associated protein 1 light chain 3ß-II (MAP1LC3B/LC3B) in mouse lung epithelial and human epithelial (H292) cells. Overexpression of WWOX led to the activation of autophagy and inhibited inflammatory responses in LPS-induced ALI cells and mouse model. More importantly, we found that WWOX interacts with mechanistic target of rapamycin [serine/threonine kinase] (mTOR) and regulates mTOR and ULK-1 signaling-mediated autophagy. Thus, reduced WWOX levels were associated with LPS-induced ALI. WWOX can activate autophagy in lung epithelial cells and protect against LPS-induced ALI, which is partly related to the mTOR-ULK1 signaling pathway.

SARS-CoV-2 Infection and C1-Esterase Inhibitor: Camouflage Pattern and New Perspective.

In Covid-19, the pathological effect of SARS-CoV-2 infection is arbitrated through direct viral toxicity, unusual immune response, endothelial dysfunction, deregulated renin-angiotensin system [RAS], and thrombo-inflammation, leading to acute lung injury (ALI), with a succession of acute respiratory distress syndrome (ARDS) in critical conditions. C1 esterase inhibitor (C1INH) is a protease inhibitor that inhibits the spontaneous activation of complement and contact systems and kinin pathway, clotting, and fibrinolytic systems. Therefore, targeting the complement system through activation of C1INH might be a novel therapeutic modality in the treatment of Covid-19. Therefore, this study aims to illustrate the potential nexus between C1INH and the pathophysiology of SARS-CoV-2 infection. C1INH is highly dysregulated in Covid-19 due to inflammatory and coagulation disorders. C1INH is up-regulated in Covid-19 and sepsis as an acute phase response, but this increase is insufficient to block the activated complement system. In addition, the C1INH serum level predicts the development of ARDS in Covid-19 patients, as its up-regulation is associated with the development of cytokine storm. In Covid-19, C1INH might be inhibited or dysregulated by SARS-CoV-2, leading to propagation of complement system activation with subsequent uncontrolled immunological stimulation due to activation of bradykinin and FXII with sequential activation of coagulation cascades and polymerization of fibrin. Thus, suppression of C1INH by SARS-CoV-2 infection leads to thrombosis and excessive inflammation due to uncontrolled activation of complements and contact systems.

Environmental Factors.

The acute respiratory distress syndrome (ARDS) remains a major cause of morbidity and mortality in the intensive care unit. Improving outcomes depends on not only evidence-based care once ARDS has already developed but also preventing ARDS incidence. Several environmental exposures have now been shown to increase the risk of ARDS and related adverse outcomes. How environmental factors impact the risk of developing ARDS is a growing and important field of research that should inform the care of individual patients as well as public health policy.

Qingwenzhike Prescription Alleviates Acute Lung Injury Induced by LPS via Inhibiting TLR4/NF-kB Pathway and NLRP3 Inflammasome Activation.

Background: Acute lung injury (ALI) is characterized by dysfunction of the alveolar epithelial membrane caused by acute inflammation and tissue injury. Qingwenzhike (QWZK) prescription has been demonstrated to be effective against respiratory viral infections in clinical practices, including coronavirus disease 2019 (COVID-19) infection. So far, the chemical compositions, protective effects on ALI, and possible anti-inflammatory mechanisms remain unknown. Methods: In this study, the compositions of QWZK were determined via the linear ion trap/electrostatic field orbital trap tandem high-resolution mass spectrometry (UHPLC-LTQ-Orbitrap MS). To test the protective effects of QWZK on ALI, an ALI model induced by lipopolysaccharide (LPS) in rats was used. The effects of QWZK on the LPS-induced ALI were evaluated by pathological changes and the number and classification of white blood cell (WBC) in bronchoalveolar lavage fluid (BALF). To investigate the possible underlying mechanisms, the contents of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein (MCP-1), interleukin-1ß (IL-1ß), interleukin-18 (IL-18), and immunoregulatory-related factors interferon-γ (IFN-γ) were detected by ELISA. Furthermore, the expression of Toll-like receptor 4 (TLR4), p-IKKα/ß, IKKα, IKKß, p-IκBα, IκBα, p-NF-κB, nuclear factor-κB (NF-κB), NOD-like receptor family pyrin domain containing 3 (NLRP3), cleaved caspase-1, pro-caspase-1, apoptosis-associated speck-like protein containing CARD (ASC), and ß-actin were tested by Western blot. Results: A total of 99 compounds were identified in QWZK, including 33 flavonoids, 23 phenolic acids, 3 alkaloids, 3 coumarins, 20 triterpenoids, 5 anthraquinones, and 12 others. ALI rats induced by LPS exhibited significant increase in neutrophile, significant decrease in lymphocyte, and evidently thicker alveolar wall than control animals. QWZK reversed the changes in WBC count and alveolar wall to normal level on the model of ALI induced by LPS. ELISA results revealed that QWZK significantly reduced the overexpression of proinflammatory factors IL-6, TNF-α, MCP-1, IL-1ß, IL-18, and IFN-γ induced by LPS. Western blot results demonstrated that QWZK significantly downregulated the overexpression of TLR4, p-IKKα/ß, p-IκBα, p-NF-κB, NLRP3, cleaved caspase-1, and ASC induced by LPS, which suggested that QWZK inhibited TLR4/NF-κB signaling pathway and NLRP3 inflammasomes. Conclusions: The chemical compositions of QWZK were first identified. It was demonstrated that QWZK showed protective effects on ALI induced by LPS. The possible underlying mechanisms of QWZK on ALI induced by LPS was via inhibiting TLR4/NF-kB signaling pathway and NLRP3 inflammasome activation. This work suggested that QWZK is a potential therapeutic candidate for the treatments of ALI and pulmonary inflammation.

Anti-histamines and Covid-19: Hype or Hope

Histamine is a biogenic amine distributed extensively in the human cells. Histamine is linked with different inflammatory and allergic disorders through promoting of chemoatractant activity and endothelial changes. Antihistamine drugs are effective in the treatment and prevention of infection of influenza H7N9 through inhibition of viral entry to the host cells. A multiplicity of search strategies including experimental, preclinical and clinical studies were taken on and assumed to review the potential role of H1, H2 or their combination in the management of Coronavirus disease 2019 (Covid-19). Histamine release is associated with early and late pathology of Covid-19 and clinical presentation. Despite the potential effect of famotidine in attenuating the pathogenesis of Covid-19, famotidine has no direct effect on the replication of SARS-CoV-2. However, azelastine (H1receptor blocker) used for allergic rhinitis as nasal spray has potential anti-SARS-CoV-2 activity comparable to that of remdesivir, lopinavir and chloroquine. Azelastine is more effective than other agents that are used in the management of Covid-19 due to significant inhibition of endosomal acidification at respiratory epithelial cells. However, famotidine and cetirizine combination improve clinical outcome and reduce intubation and duration of hospitalization in Covid-19 patients. Taken together, hospitalised Covid-19 patients treated with famotidine only showed more complications as compared with those treated with combination of famotidine and cetirizine. Conclusion: Both H1 and H2 blockade are effective in the management of Covid-19 patients through antiviral and anti-inflammatory properties, which together reduce the risk of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).

Inhibition of Prostaglandin F2α Receptors Exaggerates HCl-Induced Lung Inflammation in Mice.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe respiratory disorders that are caused by aspiration, sepsis, trauma, and pneumonia. A clinical feature of ALI/ARDS is the acute onset of severe hypoxemia, and the mortality rate, which is estimated at 38-50%, remains high. Although prostaglandins (PGs) are detected in the bronchoalveolar lavage fluid of patients with ALI/ARDS, the role of PGF2α in ALI remains unclear. We aimed to clarify the role of PGF2α/PGF2α receptor (FP) signaling in acid-induced ALI using an FP receptor antagonist, AL8810. Intratracheal injection of hydrochloric acid (HCl) increased neutrophil migration into the lungs, leading to respiratory dysfunction. Pre-administration of AL8810 further increased these features. Moreover, pre-treatment with AL8810 enhanced the HCl-induced expression of pro-inflammatory cytokines and neutrophil migratory factors in the lungs. Administration of HCl decreased the gene expression of lung surfactant proteins, which was further reduced by co-administration of AL8810. Administration of AL8810 also increased lung edema and reduced mRNA expression of epithelial sodium channel in the lungs, indicating that AL8810 reduced fluid clearance. Furthermore, AL8810 also increased lipopolysaccharide-induced expression of adhesion molecules such as intracellular adhesion molecule-1 and E-selectin in human umbilical vein endothelial cells. These results indicate that inhibition of FP receptors by AL8810 exacerbated HCl-induced ALI.

Non-clinical safety profile and pharmacodynamics of two formulations of the anti-sepsis drug candidate Rejuveinix (RJX).

Here, we demonstrate that the two distinct formulations of our anti-sepsis drug candidate Rejuveinix (RJX), have a very favorable safety profile in Wistar Albino rats at dose levels comparable to the projected clinical dose levels. 14-day treatment with RJX-P (RJX PPP.18.1051) or RJX-B (RJX-B200702-CLN) similarly elevated the day 15 tissue levels of the antioxidant enzyme superoxide dismutase (SOD) as well as ascorbic acid in both the lungs and liver in a dose-dependent fashion. The activity of SOD and ascorbic acid levels were significantly higher in tissues of RJX-P or RJX-B treated rats than vehicle-treated control rats (p < 0.0001). There was no statistically significant difference between tissue SOD activity or ascorbic acid levels of rats treated with RJX-P vs. rats treated with RJX-B (p > 0.05). The observed elevations of the SOD and ascorbic acid levels were transient and were no longer detectable on day 28 following a 14-day recovery period. These results demonstrate that RJX-P and RJX-B are bioequivalent relative to their pharmacodynamic effects on tissue SOD and ascorbic acid levels. Furthermore, both formulations showed profound protective activity in a mouse model of sepsis. In agreement with the PD evaluations in rats and their proposed mechanism of action, both RJX-P and RJX-B exhibited near-identical potent and dose-dependent anti-oxidant and anti-inflammatory activity in the LPS-GalN model of ARDS and multi-organ failure in mice.

Innate Receptor Activation Patterns Involving TLR and NLR Synergisms in COVID-19, ALI/ARDS and Sepsis Cytokine Storms: A Review and Model Making Novel Predictions and Therapeutic Suggestions.

Severe COVID-19 is characterized by a "cytokine storm", the mechanism of which is not yet understood. I propose that cytokine storms result from synergistic interactions among Toll-like receptors (TLR) and nucleotide-binding oligomerization domain-like receptors (NLR) due to combined infections of SARS-CoV-2 with other microbes, mainly bacterial and fungal. This proposition is based on eight linked types of evidence and their logical connections. (1) Severe cases of COVID-19 differ from healthy controls and mild COVID-19 patients in exhibiting increased TLR4, TLR7, TLR9 and NLRP3 activity. (2) SARS-CoV-2 and related coronaviruses activate TLR3, TLR7, RIG1 and NLRP3. (3) SARS-CoV-2 cannot, therefore, account for the innate receptor activation pattern (IRAP) found in severe COVID-19 patients. (4) Severe COVID-19 also differs from its mild form in being characterized by bacterial and fungal infections. (5) Respiratory bacterial and fungal infections activate TLR2, TLR4, TLR9 and NLRP3. (6) A combination of SARS-CoV-2 with bacterial/fungal coinfections accounts for the IRAP found in severe COVID-19 and why it differs from mild cases. (7) Notably, TLR7 (viral) and TLR4 (bacterial/fungal) synergize, TLR9 and TLR4 (both bacterial/fungal) synergize and TLR2 and TLR4 (both bacterial/fungal) synergize with NLRP3 (viral and bacterial). (8) Thus, a SARS-CoV-2-bacterium/fungus coinfection produces synergistic innate activation, resulting in the hyperinflammation characteristic of a cytokine storm. Unique clinical, experimental and therapeutic predictions (such as why melatonin is effective in treating COVID-19) are discussed, and broader implications are outlined for understanding why other syndromes such as acute lung injury, acute respiratory distress syndrome and sepsis display varied cytokine storm symptoms.

Overview of COVID-19 inflammatory pathogenesis from the therapeutic perspective.

The novel beta coronavirus (SARS-CoV-2, designated as COVID-19) that is responsible for severe acute respiratory syndrome has devastated the global economy and health care system. Since COVID-19 changed the definition of "normal" in ordinary life around the world, the development of effective therapeutics and preventive measures is desperately needed to fight SARS-CoV-2 infection and restore normalcy. A clear understanding of COVID-19 pathogenesis is crucial in providing the scientific rationale necessary to develop anti-COVID19 drugs and vaccines. According to the most recently published literature, COVID-19 pathogenesis was postulated to occur in three sequential phases: pulmonary, proinflammatory, and prothrombic. Herein, virus-host interactions, potential pathogenic mechanisms, and clinical manifestations are described for each phase. Additionally, based on this pathogenesis model, various therapeutic strategies involving current clinical trials are presented with an explanation of their modes of action and example drugs. This review is a thorough, updated summary of COVID-19 pathogenesis and the therapeutic options available for this disease.