Exploring m6A-RNA methylation as a potential therapeutic strategy for acute lung injury and acute respiratory distress syndrome.

N6-methyladenosine (m6A) is the most common methylation modification in mammalian messenger RNA (mRNA) and noncoding RNAs. m6A modification plays a role in the regulation of gene expression and deregulation of m6A methylation has been implicated in many human diseases. Recent publications suggest that exploitation of this methylation process may possess utility against acute lung injury (ALI). ALI and its more severe form, acute respiratory distress syndrome (ARDS) are acute, inflammatory clinical syndromes characterized by poor oxygenation and diffuse pulmonary infiltrates. This syndrome is associated with microvascular endothelial dysfunction, subsequent pulmonary hypertension and may ultimately lead to mortality without rigorous and acute clinical intervention. Over the years, many attempts have been made to detect novel therapeutic avenues for research without much success. The urgency for the discovery of novel therapeutic agents has become more pronounced recently given the current pandemic infection of coronavirus disease 2019 (COVID-2019), still ongoing at the time that this review is being written. We review the current landscape of literature regarding ALI and ARDS etiology, pathophysiology, and therapeutics and present a potential role of m6A methylation. Additionally, we will establish the axiomatic principles of m6A methylation to provide a framework. In conclusion, METTL3, or methyltransferase-like 3, the selective RNA methyltransferase for m6A, is a hub of proinflammatory gene expression regulation in ALI, and using a modern drug discovery strategy will identify new and effective ALI drug candidates targeting METTTL3.

SOX18-associated gene signature predicts sepsis outcome.

OBJECTIVES: Sepsis is a critical medical condition associated with an high mortality. Currently, there are no reliable diagnostic or prognostic biomarkers to evaluate sepsis outcomes. SRY (sex-determining region on the Y chromosome)-box transcription factor 18 (SOX18) is an endothelial barrier protective protein, and a decreased level of SOX18 expression is involved in disruption of human endothelial cell barrier integrity. Over-expression of SOX18 attenuates the bacterial lipopolysaccharide (LPS)-mediated disruption of the vascular barrier and is associated with favorable prognosis. The utility of SOX18-related genes as biomarkers in sepsis is uncertain. METHODS: Transcriptomic analysis was used to profile the PBMC samples of patients with sepsis across two Gene Expression Omnibus (GEO) datasets with survival data. An 84-gene signature was derived from discovery datasets that correlated with SOX18 gene expression and sepsis survival. RESULTS: Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed Th1 and Th2 cell differentiation, Cytokine-cytokine receptor interaction, and T cell receptor signaling pathways as the most significantly enriched KEGG pathways among 84 genes. A severity score based on the gene expression of 84 genes was allocated to each patient. A notable increase was detected in sepsis patients compared to healthy controls in both discovery and validation cohorts. SOX18-associated gene signature discriminated severe cases from mild cases and performed significantly better than both random 84-gene sets from whole genomes or sepsis survival-related genes. Furthermore, we obtained an 18-gene signature from screening these 84 genes in a LASSO model, which performed better in both discovery and validation cohorts. CONCLUSIONS: Data support SOX18-associated gene signatures as a prognostic biomarker for sepsis.

Anti-inflammatory Effects of Statins in Lung Vascular Pathology: From Basic Science to Clinical Trials.

HMG-CoA reductase inhibitors (or statins) are cholesterol-lowering drugs and are among the most widely prescribed medications in the United States. Statins exhibit pleiotropic effects that extend beyond cholesterol reduction including anti-atherosclerotic, antiproliferative, anti-inflammatory, and antithrombotic effects. Over the last 20 years, statins have been studied and examined in pulmonary vascular disorders, including both chronic pulmonary vascular disease such as pulmonary hypertension, and acute pulmonary vascular endothelial injury such as acute lung injury. In both research and clinical settings, statins have demonstrated promising vascular protection through modulation of the endothelium, attenuation of vascular leak, and promotion of endothelial repair following lung inflammation. This chapter provides a summary of the rapidly changing literature, summarizes the anti-inflammatory mechanism of statins on pulmonary vascular disorders, and explores clinical evidence for statins as a potential therapeutic approach to modulation of the endothelium as well as a means to broaden our understanding of pulmonary vasculopathy pathophysiology.

Identification of S1PR3 gene signature involved in survival of sepsis patients.

BACKGROUND: Sepsis is a life-threatening complication of infection that rapidly triggers tissue damage in multiple organ systems and leads to multi-organ deterioration. Up to date, prognostic biomarkers still have limitations in predicting the survival of patients with sepsis. We need to discover more prognostic biomarkers to improve the sensitivity and specificity of the prognosis of sepsis patients. Sphingosine-1-phosphate (S1P) receptor 3 (S1PR3), as one of the S1P receptors, is a prospective prognostic biomarker regulating sepsis-relevant events, including compromised vascular integrity, antigen presentation, and cytokine secretion. Until now, no S1PR3-related prognostic gene signatures for sepsis patients have been found. METHODS: This study intends to obtain an S1PR3-associated gene signature from whole blood samples to be utilized as a probable prognostic tool for patients with sepsis. RESULTS: We obtained an 18-gene S1PR3-related molecular signature (S3MS) from the intersection of S1PR3-associated genes and survival-associated genes. Numerous important immunity pathways that regulate the progression of sepsis are enriched among our 18 genes. Significantly, S3MS functions greatly in both the discovery and validation cohort. Furthermore, we demonstrated that S3MS obtains significantly better classification performance than random 18-gene signatures. CONCLUSIONS: Our results confirm the key role of S1PR3-associated genes in the development of sepsis, which will be a potential prognostic biomarker for patients with sepsis. Our results also focus on the classification performance of our S3MS as biomarkers for sepsis, which could also provide an early warning system for patients with sepsis.

A mutation found in esophageal cancer alters integrin ß4 mRNA splicing.

Integrin ß4 (CD104, mRNA: ITGß4) contributes to anchoring cells to the extracellular matrix and is regulated in many cancer types where it contributes to tumor progression. One splice variant, integrin ß4E, is poorly characterized. We extracted several mutations from tumor samples within ITGB4 near the splice site that controls ITGß4E production, and computational analysis predicted six of these would alter splicing to alter ITGß4E abundance. One of these mutations, from an esophageal squamous cell carcinoma sample, was predicted to increase splicing toward ITGß4E. We verified this effect using a minigene, and observed that integrin ß4E slows esophageal squamous cell migration while other variants enhance migration, demonstrating that integrin ß4E regulation through mutations may contribute to esophageal squamous cell tumorigenesis.

Pulmonary Endothelial Mechanical Sensing and Signaling, a Story of Focal Adhesions and Integrins in Ventilator Induced Lung Injury.

Patients with critical illness such as acute lung injury often undergo mechanical ventilation in the intensive care unit. Though lifesaving in many instances, mechanical ventilation often results in ventilator induced lung injury (VILI), characterized by overdistension of lung tissue leading to release of edemagenic agents, which further damage the lung and contribute to the mortality and progression of pulmonary inflammation. The endothelium is particularly sensitive, as VILI associated mechanical stress results in endothelial cytoskeletal rearrangement, stress fiber formation, and integrity loss. At the heart of these changes are integrin tethered focal adhesions (FAs) which participate in mechanosensing, structure, and signaling. Here, we present the known roles of FA proteins including c-Src, talin, FAK, paxillin, vinculin, and integrins in the sensing and response to cyclic stretch and VILI associated stress. Attention is given to how stretch is propagated from the extracellular matrix through integrins to talin and other FA proteins, as well as signaling cascades that include FA proteins, leading to stress fiber formation and other cellular responses. This unifying picture of FAs aids our understanding in an effort to prevent and treat VILI.