Dimethyl fumarate and 4-octyl itaconate are anticoagulants that suppress Tissue Factor in macrophages via inhibition of Type I Interferon.

Excessive inflammation-associated coagulation is a feature of infectious diseases, occurring in such conditions as bacterial sepsis and COVID-19. It can lead to disseminated intravascular coagulation, one of the leading causes of mortality worldwide. Recently, type I interferon (IFN) signaling has been shown to be required for tissue factor (TF; gene name F3) release from macrophages, a critical initiator of coagulation, providing an important mechanistic link between innate immunity and coagulation. The mechanism of release involves type I IFN-induced caspase-11 which promotes macrophage pyroptosis. Here we find that F3 is a type I IFN-stimulated gene. Furthermore, F3 induction by lipopolysaccharide (LPS) is inhibited by the anti-inflammatory agents dimethyl fumarate (DMF) and 4-octyl itaconate (4-OI). Mechanistically, inhibition of F3 by DMF and 4-OI involves suppression of Ifnb1 expression. Additionally, they block type I IFN- and caspase-11-mediated macrophage pyroptosis, and subsequent TF release. Thereby, DMF and 4-OI inhibit TF-dependent thrombin generation. In vivo, DMF and 4-OI suppress TF-dependent thrombin generation, pulmonary thromboinflammation, and lethality induced by LPS, E. coli, and S. aureus, with 4-OI additionally attenuating inflammation-associated coagulation in a model of SARS-CoV-2 infection. Our results identify the clinically approved drug DMF and the pre-clinical tool compound 4-OI as anticoagulants that inhibit TF-mediated coagulopathy via inhibition of the macrophage type I IFN-TF axis.

EGFR Signaling in Lung Fibrosis.

In this review article, we will first provide a brief overview of the ErbB receptor-ligand system and its importance in developmental and physiological processes. We will then review the literature regarding the role of ErbB receptors and their ligands in the maladaptive remodeling of lung tissue, with special emphasis on idiopathic pulmonary fibrosis (IPF). Here we will focus on the pathways and cellular processes contributing to epithelial-mesenchymal miscommunication seen in this pathology. We will also provide an overview of the in vivo studies addressing the efficacy of different ErbB signaling inhibitors in experimental models of lung injury and highlight how such studies may contribute to our understanding of ErbB biology in the lung. Finally, we will discuss what we learned from clinical applications of the ErbB1 signaling inhibitors in cancer in order to advance clinical trials in IPF.

Altered fibrin clot structure and dysregulated fibrinolysis contribute to thrombosis risk in severe COVID-19.

The high incidence of thrombotic events suggests a possible role of the contact system pathway in COVID-19 pathology. In this study, we determined the altered levels of factor XII (FXII) and its activation products in critically ill patients with COVID-19 in comparison with patients with severe acute respiratory distress syndrome related to the influenza virus (acute respiratory distress syndrome [ARDS]-influenza). Compatible with those data, we found rapid consumption of FXII in COVID-19 but not in ARDS-influenza plasma. Interestingly, the lag phase in fibrin formation, triggered by the FXII activator kaolin, was not prolonged in COVID-19, as opposed to that in ARDS-influenza. Confocal and electron microscopy showed that increased FXII activation rate, in conjunction with elevated fibrinogen levels, triggered formation of fibrinolysis-resistant, compact clots with thin fibers and small pores in COVID-19. Accordingly, clot lysis was markedly impaired in COVID-19 as opposed to that in ARDS-influenza. Dysregulated fibrinolytic system, as evidenced by elevated levels of thrombin-activatable fibrinolysis inhibitor, tissue-plasminogen activator, and plasminogen activator inhibitor-1 in COVID-19 potentiated this effect. Analysis of lung tissue sections revealed widespread extra- and intravascular compact fibrin deposits in patients with COVID-19. A compact fibrin network structure and dysregulated fibrinolysis may collectively contribute to a high incidence of thrombotic events in COVID-19.

Sex-specific differences in plasma levels of FXII, HK, and FXIIa-C1-esterase inhibitor complexes in community-acquired pneumonia.

Sex-dependent differences in immunity and coagulation play an active role in the outcome of community-acquired pneumonia (CAP). Contact phase proteins act at the crossroads between inflammation and coagulation thus representing a point of convergence in host defense against infection. Here, we measured the levels of factor XII (FXII), FXIIa-C1 esterase inhibitor (C1INH) complexes, and high-molecular-weight kininogen (HK) in plasma of patients with CAP and correlated them to clinical disease severity. Levels of FXIIa-C1INH/albumin ratio were elevated, irrespective of sex, in plasma of patients with CAP (n = 139) as compared with age-matched donors (n = 58). No simultaneous decrease in FXII levels, indicating its consumption, was observed. Stratification by sex revealed augmented FXII levels in plasma of women with CAP as compared with sex-matched donors yet no apparent differences in men. This sex-specific effect was, however, attributable to lower FXII levels in female donors relative to men donors. Plasma estradiol levels mirrored those for FXII. Levels of HK/albumin ratio were decreased in CAP plasma as compared with donors, however, after stratification by sex, this difference was only observed in women and was related to higher HK/albumin values in female donors as opposed to male donors. Finally, strong negative correlation between plasma levels of HK/albumin ratio and CAP severity, as assessed by CRB65 score, in males and females was observed. Our study identifies sex-dependent differences in plasma levels of the contact phase proteins in elderly subjects that may contribute to specific clinical outcomes in CAP between men and women.

[Beta-hydroxybutyrate measurements with the GlucoMen®LX Plus in the diagnosis of diabetic ketoacidosis in dogs and cats]. / Beta-Hydroxybutyrat-Messung mit dem GlucoMen®LX Plus zur Diagnose der diabetischen Ketoazidose bei Hunden und Katzen.

OBJECTIVE: The measurement of beta-hydroxybutyrate (BOHB) carries high significance for the diagnosis, prognosis as well as treatment decisions in canine and feline diabetic ketoacidosis. The aim of this study was to establish clinically usable cut-off values for BHOB measurements in dogs and cats using the glucometer GlucoMen®LX Plus. MATERIAL AND METHODS: We measured BOHB with the GlucoMen®LX Plus in 4 patient groups (diabetic ketoacidosis, diabetic non-ketoacidic, catabolic non-diabetic status, control). These were classified based upon medical history and laboratory findings (pH, glucose-, HCO3 - concentrations, anion gap). The data was analyzed in a ROC-curve-analysis in order to create cut-off values. RESULTS: A total of 47 dogs and 55 cats were included into the study. In the differentiation between the two diabetic groups, cut-off values for dogs and cats amounted to 2.55 mmol/l and 4.05 mmol/l, respectively. Here, good sensitivity (100 %) and specificity (82 % and 100 %, respectively) were attained. In the comparison of the catabolic non-diabetic status group and the individuals with diabetic ketosis, the analysis resulted in a cut-off value of 0.25 mmol/l in dogs and 0.25 mmol/l in cats, carrying poor sensitivity (58 % and 59 %, respectively) and specificity (90 %). CONCLUSION: Measurements with the GlucoMen®LX Plus are suitable for a reliable differentiation between ketoacidosis and ketosis in dogs and cats. Here, the determined cut-off values carried high sensitivity and specificity. A distinction between non-diabetic catabolic individuals and patients with diabetic catabolic states, however, cannot be achieved with adequate consistency. CLINICAL RELEVANCE: The established cut-off values aid in the treatment decision-making process as well as the assessment of prognosis and treatment success in diabetic ketoacidosis. In representing a point of care technique, the method allows for direct owner communication of the results and immediate adjustment of the treatment regime. Concerning the initial diagnosis or a differentiation between non-diabetic and diabetic catabolic states, however, the presented method alone is not sufficient, therefore additional diagnostic procedures are warranted in order to ascertain a correct diagnosis.

[Comparative measurement using the GlucoMen®LX PLUS and a reference method to quantify ß-hydroxybutyrate in dogs and cats]. / Vergleichsmessung mit dem GlucoMen®LX PLUS und einer Referenzmethode zur Bestimmung von ß-Hydroxybutyrat bei Hunden und Katzen.

OBJECTIVES: The detection of ketone bodies in urinary samples often underestimates the degree of ketonuria and may lead to false negative results due to the lack of detection of ß-hydroxybutyrate. In human medicine, the standard method used to quantify and monitor ketonemia is the measurement of ß-hydroxybutyrate in whole blood samples which is associated with a higher sensitivity. For this, only few devices have to date been evaluated in veterinary medicine. These have shown limitations in areas of high ß-hydroxybutyrate concentrations. The aim of the study was to compare the portable ketone meter GlucoMen®LX PLUS with a reference method for measurement of ß-hydroxybutyrate in canine and feline venous blood samples. MATERIAL AND METHODS: In this prosepctive study, a total of 47 dogs and 55 cats were enrolled. These cases comprised patients with diabetic ketoacidosis, diabetes mellitus and catabolic metabolism as well as healthy individuals. Comparison between the GlucoMen®LX PLUS ketone meter and an enzymatic reaction method by an automated chemistry analyzer was performed. Measurement results of dogs and cats were evaluated separately. RESULTS: There was a high correlation between measurement values of the GlucoMen®LX PLUS and the enzymatic reaction laboratory method in dogs (R = 0.99, p < 0.001) and cats (R = 0.98, p < 0.001). Mean difference was 0.01 mmol/l (SD ± 0.20) in dogs and 0.05 mmol/l (SD ± 0.29) in cats. In 44 % of all dogs and cats the GlucoMen®LX PLUS measured lower values in comparison to the reference method. Greater differences between the 2 measurement methods were apparent in both high and low ß-hydroxybutyrate concentration ranges (dogs, R = -0.762 and cats, R = -0.86). In high concentration areas, the GlucoMen®LX PLUS led to slightly lower results, whereas in low concentration areas slightly higher values were measured. CONCLUSION: The GlucoMen®LX PLUS shows a strong correlation with the standard reference method and is useful for measurement of ß-hydroxybutyrate in canine and feline venous blood samples. Limitations can be seen in high concentration ranges of ß-hydroxybutyrate in which the GlucoMen®LX PLUS resulted in slightly lower measurement values. CLINICAL RELEVANCE: The GlucoMen®LX PLUS is a cost-effective portable device representing a viable alternative to urinary ketone body measurement.