Targeting a mean arterial pressure of 80 to 85 mm Hg, as compared with 65 to 70 mm Hg, in patients with septic shock undergoing resuscitation did not result in significant differences in mortality at either 28 or 90 days. (Funded by the French Ministry of Health; SEPSISPAM ClinicalTrials.gov number, NCT01149278.).

Immunological functions of mast cells remain poorly understood. Studies in Kit mutant mice suggest key roles for mast cells in certain antibody- and T cell-mediated autoimmune diseases. However, Kit mutations affect multiple cell types of both immune and nonimmune origin. Here, we show that targeted insertion of Cre-recombinase into the mast cell carboxypeptidase A3 locus deleted mast cells in connective and mucosal tissues by a genotoxic Trp53-dependent mechanism. Cre-mediated mast cell eradication (Cre-Master) mice had, with the exception of a lack of mast cells and reduced basophils, a normal immune system. Cre-Master mice were refractory to IgE-mediated anaphylaxis, and this defect was rescued by mast cell reconstitution. This mast cell-deficient strain was fully susceptible to antibody-induced autoimmune arthritis and to experimental autoimmune encephalomyelitis. Differences comparing Kit mutant mast cell deficiency models to selectively mast cell-deficient mice call for a systematic re-evaluation of immunological functions of mast cells beyond allergy.

Growing clinical evidence has implicated complement as a pivotal driver of COVID-19 immunopathology. Deregulated complement activation may fuel cytokine-driven hyper-inflammation, thrombotic microangiopathy and NET-driven immunothrombosis, thereby leading to multi-organ failure. Complement therapeutics have gained traction as candidate drugs for countering the detrimental consequences of SARS-CoV-2 infection. Whether blockade of terminal complement effectors (C5, C5a, or C5aR1) may elicit similar outcomes to upstream intervention at the level of C3 remains debated. Here we compare the efficacy of the C5-targeting monoclonal antibody eculizumab with that of the compstatin-based C3-targeted drug candidate AMY-101 in small independent cohorts of severe COVID-19 patients. Our exploratory study indicates that therapeutic complement inhibition abrogates COVID-19 hyper-inflammation. Both C3 and C5 inhibitors elicit a robust anti-inflammatory response, reflected by a steep decline in C-reactive protein and IL-6 levels, marked lung function improvement, and resolution of SARS-CoV-2-associated acute respiratory distress syndrome (ARDS). C3 inhibition afforded broader therapeutic control in COVID-19 patients by attenuating both C3a and sC5b-9 generation and preventing FB consumption. This broader inhibitory profile was associated with a more robust decline of neutrophil counts, attenuated neutrophil extracellular trap (NET) release, faster serum LDH decline, and more prominent lymphocyte recovery. These early clinical results offer important insights into the differential mechanistic basis and underlying biology of C3 and C5 inhibition in COVID-19 and point to a broader pathogenic involvement of C3-mediated pathways in thromboinflammation. They also support the evaluation of these complement-targeting agents as COVID-19 therapeutics in large prospective trials.

No abstract

Until now, catecholamines were the drugs of choice to treat hypotension during shock states. Catecholamines, however, also have marked metabolic effects, particularly on glucose metabolism, and the degree of this metabolic response is directly related to the beta2-adrenoceptor activity of the individual compound used. Under physiologic conditions, infusing catecholamine is associated with enhanced rates of aerobic glycolysis (resulting in adenosine triphosphate production), glucose release (both from glycogenolysis and gluconeogenesis), and inhibition of insulin-mediated glycogenesis. Consequently, hyperglycemia and hyperlactatemia are the hallmarks of this metabolic response. Under pathophysiologic conditions, the metabolic effects of catecholamines are less predictable because of changes in receptor affinity and density and in drug kinetics and the metabolic capacity of the major gluconeogenic organs, both resulting from the disease per se and the ongoing treatment. It is also well-established that shock states are characterized by a hypermetabolic condition with insulin resistance and increased oxygen demands, which coincide with both compromised tissue microcirculatory perfusion and mitochondrial dysfunction. This, in turn, causes impaired glucose utilization and may lead to inadequate glucose supply and, ultimately, metabolic failure. Based on the landmark studies on intensive insulin use, a crucial role is currently attributed to glucose homeostasis. This article reviews the effects of the various catecholamines on glucose utilization, both under physiologic conditions, as well as during shock states. Because, to date (to our knowledge), no patient data are available, results from relevant animal experiments are discussed. In addition, potential strategies are outlined to influence the catecholamine-induced effects on glucose homeostasis.