Transpulmonary Plasma Endothelin-1 Arterial:Venous Ratio Differentiates Survivors from Non-Survivors in Critically Ill Patients with COVID-19-Induced Acute Respiratory Distress Syndrome.

Endothelin-1 (ET-1) is a potent vasoconstrictor produced by endothelial cells and cleared from circulating blood mainly in the pulmonary vasculature. In a healthy pulmonary circulation, the rate of local production of ET-1 is less than its rate of clearance. In the present study, we aimed to investigate whether the abnormal pulmonary circulatory handling of ET-1 relates to poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19)-induced acute respiratory distress syndrome (ARDS). To this end, central venous and systemic arterial ET-1 plasma levels were simultaneously measured on Days 1 and 3 following ICU admission in mechanically ventilated COVID-19 patients with ARDS (COVID-19 ARDS, N = 18). Central venous and systemic arterial ET-1 plasma levels were also measured in two distinct SARS-CoV-2-negative mechanically ventilated critically ill patient groups, matched for age, sex, and critical illness severity, with ARDS (non-COVID-19 ARDS, N = 14) or without ARDS (non-COVID-19 non-ARDS, N = 20). Upon ICU admission, COVID-19-induced ARDS patients had higher systemic arterial and central venous ET-1 levels compared to the non-COVID-19 ARDS and non-COVID-19 non-ARDS patients (p < 0.05), yet a normal systemic arterial:central venous (A:V) ET-1 ratio [0.63 (0.49-1.02)], suggesting that pulmonary ET-1 clearance is intact in these patients. On the other hand, the non-COVID-19 ARDS patients demonstrated abnormal ET-1 handling [A:V ET-1 ratio 1.06 (0.93-1.20)], while the non-COVID-19 non-ARDS group showed normal ET-1 handling [0.79 (0.52-1.11)]. On Day 3, the A:V ratio in all three groups was <1. When the COVID-19 ARDS patients were divided based on 28-day ICU mortality, while their systemic arterial and central venous levels did not differ, the A:V ET-1 ratio was statistically significantly higher upon ICU admission in the non-survivors [0.95 (0.78-1.34)] compared to the survivors [0.57 (0.48-0.92), p = 0.027]. Our results highlight the potential importance of ET-1 as both a biomarker and a therapeutic target in critically ill COVID-19 patients. The elevated A:V ET-1 ratio in non-survivors suggests that the early disruption of pulmonary ET-1 handling may be a key marker of poor prognosis.

Effects of Modulating BMP9, BMPR2, and AQP1 on BMP Signaling in Human Pulmonary Microvascular Endothelial Cells.

Pulmonary arterial hypertension (PAH) is a chronic disease characterized by a progressive increase in mean pulmonary arterial pressure. Mutations in the BMPR2 and AQP1 genes have been described in familial PAH. The bone morphogenetic proteins BMP9 and BMP10 bind with high affinity to BMPR2. Administration of BMP9 has been proposed as a potential therapeutic strategy against PAH, although recent conflicting evidence dispute the effect of such a practice. Considering the involvement of the above molecules in PAH onset, progression, and therapeutic value, we examined the effects of modulation of BMP9, BMPR2, and AQP1 on BMP9, BMP10, BMPR2, AQP1, and TGFB1 expression in human pulmonary microvascular endothelial cells in vitro. Our results demonstrated that silencing the BMPR2 gene resulted in increased expression of its two main ligands, namely BMP9 and BMP10. Exogenous administration of BMP9 caused the return of BMP10 to basal levels, while it restored the decreased AQP1 protein levels and the decreased TGFB1 mRNA and protein expression levels caused by BMPR2 silencing. Moreover, AQP1 gene silencing also resulted in increased expression of BMP9 and BMP10. Our results might possibly imply that the effect of exogenously administered BMP9 on molecules participating in the BMP signaling pathway could depend on the expression levels of BMPR2. Taken together, these results may provide insight into the highly complex interactions of the BMP signaling pathway.

Increased Levels of Galectin-3 in Critical COVID-19.

Severe COVID-19 is related to hyperinflammation and multiple organ injury, including respiratory failure, thus requiring intensive care unit (ICU) admission. Galectin-3, a carbohydrate-binding protein exhibiting pleiotropic effects, has been previously recognized to participate in inflammation, the immune response to infections and fibrosis. The aim of this study was to evaluate the relationship between galectin-3 and the clinical severity of COVID-19, as well as assess the prognostic accuracy of galectin-3 for the probability of ICU mortality. The study included 235 COVID-19 patients with active disease, treated in two different Greek hospitals in total. Our results showed that median galectin-3 serum levels on admission were significantly increased in critical COVID-19 patients (7.2 ng/mL), as compared to the median levels of patients with less severe disease (2.9 ng/mL, p = 0.003). Galectin-3 levels of the non-survivors hospitalized in the ICU were significantly higher than those of the survivors (median 9.1 ng/mL versus 5.8 ng/mL, p = 0.001). The prognostic accuracy of galectin-3 for the probability of ICU mortality was studied with a receiver operating characteristic (ROC) curve and a multivariate analysis further demonstrated that galectin-3 concentration at hospital admission could be assumed as an independent risk factor associated with ICU mortality. Our results were validated with galectin-3 measurements in a second patient cohort from a different Greek university hospital. Our results, apart from strongly confirming and advancing previous knowledge with two patient cohorts, explore the possibility of predicting ICU mortality, which could provide useful information to clinicians. Therefore, galectin-3 seems to establish its involvement in the prognosis of hospitalized COVID-19 patients, suggesting that it could serve as a promising biomarker in critical COVID-19.

Persistent Endothelial Lung Damage and Impaired Diffusion Capacity in Long COVID.

Since the beginning of the pandemic, both COVID-19-associated coagulopathy biomarkers and a plethora of endothelial biomarkers have been proposed and tested as prognostic tools of severity and mortality prediction. As the pandemic is gradually being controlled, attention is now focusing on the long-term sequelae of COVID-19. In the present study, we investigated the role of endothelial activation/dysfunction in long COVID syndrome. This observational study included 68 consecutive long COVID patients and a healthy age and sex-matched control group. In both groups, we measured 13 endothelial biomarkers. Moreover, in the long COVID patients, we evaluated fatigue and dyspnea severity, lung diffusion capacity (DLCO), and the 6-min walk (6MWT) test as measures of functional capacity. Our results showed that markers of endothelial activation/dysfunction were higher in long COVID patients, and that soluble intracellular adhesion molecule 1 (sICAM-1) and soluble vascular adhesion molecule 1 (sVCAM-1) negatively correlated with lung diffusion and functional capacity (sICAM-1 vs. DLCO, r = -0.306, p = 0.018; vs. 6MWT, r = -0.263, p = 0.044; and sVCAM-1 vs. DLCO, r= -0.346, p = 0.008; vs. 6MWT, r = -0.504, p < 0.0001). In conclusion, evaluating endothelial biomarkers alongside clinical tests might yield more specific insights into the pathophysiological mechanisms of long COVID manifestations.

Prognostic Value of HIF-1α-Induced Genes in Sepsis/Septic Shock.

Hypoxia is characterized as one of the main consequences of sepsis, which is recognized as the leading cause of death in intensive care unit (ICU) patients. In this study, we aimed to examine whether the expression levels of genes regulated under hypoxia could be utilized as novel biomarkers for sepsis prognosis in ICU patients. Whole blood expression levels of hypoxia-inducible factor-1α (HIF1A), interferon-stimulated gene 15 (ISG15), hexokinase 2 (HK2), lactate dehydrogenase (LDHA), heme oxygenase-1 (HMOX1), erythropoietin (EPO), and the vascular endothelial growth factor A (VEGFA) were measured on ICU admission in 46 critically ill, initially non-septic patients. The patients were subsequently divided into two groups, based on the development of sepsis and septic shock (n = 25) or lack thereof (n = 21). HMOX1 mRNA expression was increased in patients who developed sepsis/septic shock compared to the non-septic group (p < 0.0001). The ROC curve, multivariate logistic regression, and Kaplan-Meier analysis demonstrated that HMOX1 expression could be utilized for sepsis and septic shock development probability. Overall, our results indicate that HMOX1 mRNA levels have the potential to be a valuable predictive factor for the prognosis of sepsis and septic shock in ICU patients.

Investigation of Serum Endocan Levels and Age in Critical Inflammatory Conditions.

Aging negatively affects the endothelium. Endocan (ESM-1), an endothelium-derived soluble proteoglycan, participates in fundamental biological processes of endothelial cells. We aimed to examine the role of endothelial dysfunction and age in poor outcomes in critical illness. ESM-1 levels were measured in the sera of mechanically ventilated critically ill patients, including COVID-19, non-septic, and septic patients. The 3 patient cohorts were divided based on age (≥65 and <65). Critically ill COVID-19 patients had statistically higher ESM-1 levels compared to critically ill septic and non-septic patients. Only in critically ill septic patients were ESM-1 levels higher in older compared to younger patients. Finally, the age-subgrouped patients were further subdivided based on intensive care unit (ICU) outcome. ESM-1 levels were similar in COVID-19 survivors and non-survivors, irrespective of age. Interestingly, only for the younger critically ill septic patients, non-survivors had higher ESM-1 levels compared to survivors. In the non-septic survivors and non-survivors, ESM-1 levels remained unaltered in the younger patients and tended to be higher in the elderly. Even though endocan has been recognized as an important prognostic biomarker in critically ill patients with sepsis, in our patient cohort, increased age, as well as the extent of endothelial dysfunction, seemed to affect its prognostic ability.

Endotheliopathy in Acute COVID-19 and Long COVID.

The pulmonary endothelium is a highly regulated organ that performs a wide range of functions under physiological and pathological conditions. Since endothelial dysfunction has been demonstrated to play a direct role in sepsis and acute respiratory distress syndrome, its role in COVID-19 has also been extensively investigated. Indeed, apart from the COVID-19-associated coagulopathy biomarkers, new biomarkers were recognised early during the pandemic, including markers of endothelial cell activation or injury. We systematically searched the literature up to 10 March 2023 for studies examining the association between acute and long COVID-19 severity and outcomes and endothelial biomarkers.

NEW INSIGHTS INTO THE PATHOPHYSIOLOGY OF TRAUMA AND HEMORRHAGE.

ABSTRACT: Circulatory shock from trauma and hemorrhage remains a clinical challenge with mortality still high within the first hours after impact. It represents a complex disease involving the impairment of a number of physiological systems and organs and the interaction of different pathological mechanisms. Multiple external and patient-specific factors may further modulate and complicate the clinical course. Recently, novel targets and models with complex multiscale interaction of data from different sources have been identified which offer new windows of opportunity. Future works needs to consider patient-specific conditions and outcomes to mount shock research onto the next higher level of precision and personalized medicine.

Aquaporin Expression and Regulation in Clinical and Experimental Sepsis.

Sepsis is an inflammatory disorder caused by the host's dysfunctional response to infection. Septic patients present diverse clinical characteristics, and in the recent years, it has been the main cause of death in intensive care units (ICU). Aquaporins, membrane proteins with a role in water transportation, have been reported to participate in numerous biological processes. Their role in sepsis progression has been studied extensively. This review aims to examine recent literature on aquaporin expression and regulation in clinical sepsis, as well as established experimental models of sepsis. We will present how sepsis affects aquaporin expression at the molecular and protein level. Moreover, we will delve into the importance of aquaporin regulation at transcriptional, post-transcriptional, translational, and post-translational levels in sepsis by presenting data on aquaporin regulation by non-coding RNAs and selected chemical molecules. Finally, we will focus on the importance of aquaporin single-nucleotide polymorphisms in the setting of sepsis.

COMPARATIVE EVALUATION AND PROGNOSTIC UTILITY OF NEURONAL INJURY BIOMARKERS IN COVID-19 PATIENTS: A PROSPECTIVE STUDY.

ABSTRACT: Background : COVID-19 disease severity markers include mostly molecules related to not only tissue perfusion, inflammation, and thrombosis, but also biomarkers of neural injury. Clinical and basic research has demonstrated that SARS-COV-2 affects the central nervous system. The aims of the present study were to investigate the role of neural injury biomarkers and to compare them with inflammatory markers in their predictive ability of mortality. Methods : We conducted a prospective observational study in critically ill patients with COVID-19 and in a cohort of patients with moderate/severe disease. S100b, neuron-specific enolase (NSE), and inflammatory markers, including soluble urokinase plasminogen activator receptor (suPAR), were measured on intensive care unit or ward admission, respectively. Statistical comparisons between patient groups were performed for all biomarkers under investigation. Correlations between different biomarkers were tested with Spearman correlation coefficient. Receiver operating characteristic curves were plotted using mortality as the classification variable and the biomarker levels on admission as the prognostic variables. Results : A total of 70 patients with COVID-19 were included in the final analysis. Of all studied biomarkers, s100b had the best predictive ability for death in the intensive care unit, with an area under the curve of 0.73 (0.61-0.83), P = 0.0003. S100b levels correlated with NSE, interleukin (IL)-8, and IL-10 (0.27 < rs < 0.37, P < 0.05), and tended to correlate with suPAR ( rs = 0.26, P = 0.05), but not with the vasopressor dose ( P = 0.62). Conclusion : Among the investigated biomarkers, s100b demonstrated the best predictive ability for death in COVID-19 patients. The overall biomarker profile of the patients implies direct involvement of the nervous system by the novel coronavirus.

Family Burden of ICU Survivors and Correlations with Patient Quality of Life and Psychometric Scores - A Pilot Study.

Introduction: Post intensive care syndrome (PICS) affects an increasing number of critical illness survivors and their families, with serious physical and psychological sequelae. Since little is known about the burden of critical illness on ICU survivor families, we conducted a prospective observational study aiming to assess this, and investigate correlations of the patients' psychometric and health-related quality of life (HRQOL) scores with family burden. Materials and Methods: Twenty-nine patients were evaluated in the presence of a family member. Participants were assessed with the use of validated scales for anxiety, depression, post-traumatic stress disorder, cognitive decline, and the family burden scale (FBS). Results: High burden was present in 27.6% of family members. Statistically significant correlations were observed between the FBS score and trait anxiety, depression, and the physical and psychological components of HRQOL. Conclusions: Our results suggest that family burden following critical illness is common, suggesting that its assessment should be incorporated in the evaluation of PICS-family in large observational studies.

Acute Kidney Injury Predictors and Outcomes after Cardiac Surgery in Children with Congenital Heart Disease: An Observational Cohort Study.

Acute Kidney Injury (AKI) commonly complicates cardiac surgery in children with congenital heart disease (CHD). In this study we assessed incidence, risk factors, and outcomes of postoperative AKI, while testing the hypothesis that, depending on the underlying diagnosis, there would be significant differences in AKI incidence among different diagnostic groups. We conducted an observational cohort study of children with CHD undergoing cardiac surgery in a single tertiary center between January 2019 and August 2021 (n = 362). Kidney Disease Improving Global Outcome (KDIGO) criteria were used to determine the incidence of postoperative AKI. Diagnosis was incorporated into multivariate models using an anatomic-based CHD classification system. Overall survival was estimated using Kaplan−Meier curves. Log-rank test and adjusted Cox proportional hazard modelling were used to test for differences in survival distributions and determine AKI effect on survival function, respectively. AKI occurred in 70 (19.3%), with 21.4% in-hospital mortality for AKI group. Younger age, lower weight, longer cardiopulmonary bypass time, preoperative mechanical ventilation and diagnostic category were associated with postoperative AKI. Resolution rate was 92.7% prior to hospital discharge for survivors. AKI was associated with longer duration of mechanical ventilation, ICU and hospital length of stay. AKI patients had significantly higher probability of all-cause mortality postoperatively when compared to the non-AKI group (log-rank test, p < 0.001). Adjusted hazard ratio for AKI versus non-AKI group was 11.08 (95% CI 2.45−50.01; p = 0.002). Diagnostic category was associated with cardiac surgery-related AKI in children with CHD, a finding supporting the development of lesion specific models for risk stratification. Postoperative AKI had detrimental impact on clinical outcomes and was associated with decreased survival to hospital discharge.

Pulmonary Hypertension: Current Diagnosis, Approach and Treatment at the Dawn of the New European Guidelines.

A turning point in the field of pulmonary hypertension (PH) is the most recent publication of the new European Guidelines for the diagnosis and treatment of pulmonary hypertension, a collaboration between the European Society of Cardiology and the European Respiratory Society [...].

The Interplay between Aquaporin-1 and the Hypoxia-Inducible Factor 1α in a Lipopolysaccharide-Induced Lung Injury Model in Human Pulmonary Microvascular Endothelial Cells.

Aquaporin-1 (AQP1), a water channel, and the hypoxia-inducible factor 1α (HIF1A) are implicated in acute lung injury responses, modulating among others pulmonary vascular leakage. We hypothesized that the AQP1 and HIF1A systems interact, affecting mRNA, protein levels and function of AQP1 in human pulmonary microvascular endothelial cells (HPMECs) exposed to lipopolysaccharide (LPS). Moreover, the role of AQP1 in apoptosis and wound healing progression was examined. Both AQP1 mRNA and protein expression levels were higher in HPMECs exposed to LPS compared to untreated HPMECs. However, in the LPS-exposed HIF1A-silenced cells, the mRNA and protein expression levels of AQP1 remained unaltered. In the permeability experiments, a statistically significant volume increase was observed at the 360 s time-point in the LPS-exposed HPMECs, while LPS-exposed HIF1A-silenced HPMECs did not exhibit cell swelling, implying a dysfunctional AQP1. AQP1 did not seem to affect cell apoptosis yet could interfere with endothelial migration and/or proliferation. Based on our results, it seems that HIF1A silencing negatively affects AQP1 mRNA and protein expression, as well as AQP1 function, in the setting of lung injury.

C3a and C5b-9 Differentially Predict COVID-19 Progression and Outcome.

SARS-CoV-2 infection may result in severe pneumonia leading to mechanical ventilation and intensive care (ICU) treatment. Complement activation was verified in COVID-19 and implicated as a contributor to COVID-19 pathogenesis. This study assessed the predictive potential of complement factors C3a and C5b-9 for COVID-19 progression and outcome. We grouped 80 COVID-19 patients into severe COVID-19 patients (n = 38) and critically ill (n = 42) and subdivided into non-intubated (n = 48) and intubated (n = 32), survivors (n = 57) and non-survivors (n = 23). Results: A significant increase for C3a and C5b-9 levels was observed between: severely and critically ill patients (p < 0.001 and p < 0.0001), non-intubated vs intubated (p < 0.001 and p < 0.05), survivors vs non-survivors (p < 0.001 and p < 0.01). ROC analysis for the need for ICU treatment revealed a higher AUC for C5b-9 (0.764, p < 0.001) compared to C3a (AUC = 0.739, p < 0.01). A higher AUC was observed for C3a for the need for intubation (AUC = 0.722, p < 0.001) or mortality (AUC = 0.740, p < 0.0001) compared to C5b-9 (need for intubation AUC = 0.656, p < 0.05 and mortality AUC = 0.631, p = NS). Combining the two markers revealed a powerful prediction tool for ICU admission (AUC = 0.773, p < 0.0001), intubation (AUC = 0.756, p < 0.0001) and mortality (AUC = 0.753, p < 0.001). C3a and C5b-9 may be considered as prognostic tools separately or in combination for the progression and outcome of COVID-19.

The Paradox of Pulmonary Vascular Resistance: Restoration of Pulmonary Capillary Recruitment as a Sine Qua Non for True Therapeutic Success in Pulmonary Arterial Hypertension.

Exercise-induced increases in pulmonary blood flow normally increase pulmonary arterial pressure only minimally, largely due to a reserve of pulmonary capillaries that are available for recruitment to carry the flow. In pulmonary arterial hypertension, due to precapillary arteriolar obstruction, such recruitment is greatly reduced. In exercising pulmonary arterial hypertension patients, pulmonary arterial pressure remains high and may even increase further. Current pulmonary arterial hypertension therapies, acting principally as vasodilators, decrease calculated pulmonary vascular resistance by increasing pulmonary blood flow but have a minimal effect in lowering pulmonary arterial pressure and do not restore significant capillary recruitment. Novel pulmonary arterial hypertension therapies that have mainly antiproliferative properties are being developed to try and diminish proliferative cellular obstruction in precapillary arterioles. If effective, those agents should restore capillary recruitment and, during exercise testing, pulmonary arterial pressure should remain low despite increasing pulmonary blood flow. The effectiveness of every novel therapy for pulmonary arterial hypertension should be evaluated not only at rest, but with measurement of exercise pulmonary hemodynamics during clinical trials.

Pulmonary Vascular Research Institute GoDeep: A meta-registry merging deep phenotyping datafrom international PH reference centers.

The Pulmonary Vascular Research Institute GoDeep meta-registry is a collaboration of pulmonary hypertension (PH) reference centers across the globe. Merging worldwide PH data in a central meta-registry to allow advanced analysis of the heterogeneity of PH and its groups/subgroups on a worldwide geographical, ethnical, and etiological landscape (ClinTrial. gov NCT05329714). Retrospective and prospective PH patient data (diagnosis based on catheterization; individuals with exclusion of PH are included as a comparator group) are mapped to a common clinical parameter set of more than 350 items, anonymized and electronically exported to a central server. Use and access is decided by the GoDeep steering board, where each center has one vote. As of April 2022, GoDeep comprised 15,742 individuals with 1.9 million data points from eight PH centers. Geographic distribution comprises 3990 enrollees (25%) from America and 11,752 (75%) from Europe. Eighty-nine perecent were diagnosed with PH and 11% were classified as not PH and provided a comparator group. The retrospective observation period is an average of 3.5 years (standard error of the mean 0.04), with 1159 PH patients followed for over 10 years. Pulmonary arterial hypertension represents the largest PH group (42.6%), followed by Group 2 (21.7%), Group 3 (17.3%), Group 4 (15.2%), and Group 5 (3.3%). The age distribution spans several decades, with patients 60 years or older comprising 60%. The majority of patients met an intermediate risk profile upon diagnosis. Data entry from a further six centers is ongoing, and negotiations with >10 centers worldwide have commenced. Using electronic interface-based automated retrospective and prospective data transfer, GoDeep aims to provide in-depth epidemiological and etiological understanding of PH and its various groups/subgroups on a global scale, offering insights for improved management.

The Antifibrotic Effects of Inhaled Treprostinil: An Emerging Option for ILD.

Interstitial lung diseases (ILD) encompasses a heterogeneous group of parenchymal lung diseases characterized by variable amounts of inflammation and fibrosis. The targeting of fibroblasts and myofibroblasts with antifibrotic treatments is a potential therapeutic target for these potentially fatal diseases. Treprostinil is unique among the prostacyclin mimetics in that it has distinct actions at additional prostaglandin receptors. Preclinical and clinical evidence suggests that treprostinil has antifibrotic effects through the activation of the prostaglandin E receptor 2 (EP2), the prostaglandin D receptor 1 (DP1), and peroxisome proliferator-activated receptors (PPAR). In vivo studies of EP2 and the DP1 have found that administration of treprostinil resulted in a reduction in cell proliferation, reduced collagen secretion and synthesis, and reduced lung inflammation and fibrosis. In vitro and in vivo studies of PPARß and PPARγ demonstrated that treprostinil inhibited fibroblast proliferation in a dose-dependent manner. Clinical data from a post hoc analysis of the INCREASE trial found that inhaled treprostinil improved forced vital capacity in the overall population as well as in idiopathic interstitial pneumonia and idiopathic pulmonary fibrosis subgroups. These preclinical and clinical findings suggest a dual benefit of treprostinil through the amelioration of both lung fibrosis and pulmonary hypertension.

Increase of HO-1 Expression in Critically Ill COVID-19 Patients Is Associated with Poor Prognosis and Outcome.

Heme-oxygenase (HO)-1 is a cytoprotective enzyme with strong antioxidant and anti-apoptotic properties and previous reports have also emphasized the antiviral properties of HO-1, either directly or via induction of interferons. To investigate the potential role of HO-1 in patients with coronavirus disease 2019 (COVID-19), the present study assessed changes in HO-1 expression in whole blood and tissue samples. Upregulation of HO-1 protein was observed in lung, liver, and skin tissue independently of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presence. A significant increase of blood HO-1 mRNA levels was observed in critically ill COVID-19 patients compared to those in severe COVID-19 patients and healthy controls. This increase was accompanied by significantly elevated levels of serum ferritin and bilirubin in critically ill compared to patients with severe disease. Further grouping of patients in survivors and non-survivors revealed a significant increase of blood HO-1 mRNA levels in the later. Receiver operating characteristic (ROC) analysis for prediction of ICU admission and mortality yielded an AUC of 0.705 (p = 0.016) and 0.789 (p = 0.007) respectively indicating that HO-1 increase is associated with poor COVID-19 progression and outcome. The increase in HO-1 expression observed in critically ill COVID-19 patients could serve as a mechanism to counteract increased heme levels driving coagulation and thrombosis or as an induced protective mechanism.

Autotaxin Has a Negative Role in Systemic Inflammation.

The pathogenesis of sepsis involves complex interactions and a systemic inflammatory response leading eventually to multiorgan failure. Autotaxin (ATX, ENPP2) is a secreted glycoprotein largely responsible for the extracellular production of lysophosphatidic acid (LPA), which exerts multiple effects in almost all cell types through its at least six G-protein-coupled LPA receptors (LPARs). Here, we investigated a possible role of the ATX/LPA axis in sepsis in an animal model of endotoxemia as well as in septic patients. Mice with 50% reduced serum ATX levels showed improved survival upon lipopolysaccharide (LPS) stimulation compared to their littermate controls. Similarly, mice bearing the inducible inactivation of ATX and presenting with >70% decreased ATX levels were even more protected against LPS-induced endotoxemia; however, no significant effects were observed upon the chronic and systemic transgenic overexpression of ATX. Moreover, the genetic deletion of LPA receptors 1 and 2 did not significantly affect the severity of the modelled disease, suggesting that alternative receptors may mediate LPA effects upon sepsis. In translation, ATX levels were found to be elevated in the sera of critically ill patients with sepsis in comparison with their baseline levels upon ICU admission. Therefore, the results indicate a role for ATX in LPS-induced sepsis and suggest possible therapeutic benefits of pharmacologically targeting ATX in severe, systemic inflammatory disorders.