Ulrike Heinicke

Background: Severe progression of COVID-19 to critical illness, with pulmonary failure, multiple organ failure, and death, is driven by systemic inflammatory responses with overproduction of inflammatory cytokines. In the past years, the potential role of bradykinin, leading to inappropriate immune responses in the pathogenesis of COVID-19, has been raised in a so-called bradykinin storm. However, clinical investigations of bradykinin, its metabolite des-Arg⁹-bradykinin, or substance P, are rare or completely lacking during intensive care of COVID-19 patients. A prospective prolonged cohort study was conducted, including 44 COVID-19 patients (09/2020–02/2021, prevalent wildtype SARS-CoV-2) from the intensive care unit. Plasma levels of bradykinin, des-Arg⁹-bradykinin, and substance P were measured daily by ELISA in survivors (n = 21) and nonsurvivors (n = 23) of COVID-19 from admission until discharge or death. Results: We found significantly higher plasma levels of des-Arg⁹-bradykinin in survivors and nonsurvivors of COVID-19 compared with healthy controls. In addition, plasma des-Arg⁹-bradykinin levels were higher (P < 0.001, effect size = 0.79) in nonsurvivors compared with survivors of COVID-19 and correlated significantly with disease worsening, and clinical parameters of inflammation, like leukocyte count, IL-6 or lactate dehydrogenase, and outcome. Consequently, compared with healthy controls, bradykinin and substance P plasma levels were significantly reduced in survivors and nonsurvivors of COVID-19. Furthermore, plasma substance P levels were significantly reduced (P < 0.001, effect size = 0.7) in nonsurvivors compared with survivors of COVID-19, whereas plasma bradykinin levels did not significantly differ between survivors and nonsurvivors of COVID-19. Conclusion: Our data demonstrates that des-Arg⁹-bradykinin is significantly elevated in COVID-19 intensive care unit patients and is associated with disease severity, clinical inflammatory parameters, and survival. These results indicate that des-Arg⁹-bradykinin, not bradykinin, is one of the pivotal peptides of concern for the lethal COVID-19 aggravation and outcome. Further investigations are necessary to evaluate whether des-Arg⁹-bradykinin exhibits potent blood biomarker properties in COVID-19 and offer new treatment approaches.

Background: Severe progression of coronavirus disease 2019 (COVID-19) causes respiratory failure and critical illness. Recently, COVID-19 has been associated with heparanase (HPSE)-induced endothelial barrier dysfunction and inflammation, so called endothelitis, and therapeutic treatment with heparin or low-molecular-weight heparin (LMWH) targeting HPSE has been postulated. Because, up to this date, clinicians are unable to measure the severity of endothelitis, which can lead to multiorgan failure and concomitant death, we investigated plasma levels of HPSE and heparin-binding protein (HBP) in COVID-19 intensive care patients to render a possible link between endothelitis and these plasma parameters. Therefore, a prospective prolonged cohort study was conducted, including 47 COVID-19 patients from the intensive care unit. Plasma levels of HPSE, and HBP were measured daily by enzyme-linked immunosorbent assay in survivors (n = 35) and nonsurvivors (n = 12) of COVID-19 from admission until discharge or death. All patients were either treated with heparin or LMWH, aiming for an activated partial thromboplastin time of ≥60 seconds or an anti-Xa level of >0.8 IU/mL using enoxaparin, depending on the clinical status of the patient (patients with extracorporeal membrane oxygenation or >0.1 μg/kg/min noradrenaline received heparin, all others enoxaparin). Results: We found significantly higher plasma levels of HPSE and HBP in survivors and nonsurvivors of COVID-19, compared with healthy controls. Still, interestingly, plasma HPSE levels were significantly higher (P < 0.001) in survivors compared with nonsurvivors of COVID-19. In contrast, plasma HBP levels were significantly reduced (P < 0.001) in survivors compared with nonsurvivors of COVID-19. Furthermore, when patients received heparin, they had significantly lower HPSE (P = 2.22e − 16) and significantly higher HBP (P = 0.00013) plasma levels as when they received LMWH. Conclusion: Our results demonstrated that patients, who recover from COVID-19–induced vascular and pulmonary damage and were discharged from the intensive care unit, have significantly higher plasma HPSE level than patients who succumb to COVID-19. Therefore, HPSE is not suitable as marker for disease severity in COVID-19 but maybe as marker for patient's recovery. In addition, patients receiving therapeutic heparin treatment displayed significantly lower heparanse plasma level than upon therapeutic treatment with LMWH.

Acute respiratory distress syndrome (ARDS) is a major cause of patient mortality in intensive care units (ICUs) worldwide. Considering that no causative treatment but only symptomatic care is available, it is obvious that there is a high unmet medical need for a new therapeutic concept. One reason for a missing etiologic therapy strategy is the multifactorial origin of ARDS, which leads to a large heterogeneity of patients. This review summarizes the various kinds of ARDS onset with a special focus on the role of reactive oxygen species (ROS), which are generally linked to ARDS development and progression. Taking a closer look at the data which already have been established in mouse models, this review finally proposes the translation of these results on successful antioxidant use in a personalized approach to the ICU patient as a potential adjuvant to standard ARDS treatment.

The transcription factor NF-E2 p45-related factor 2 (Nrf2) is an established master regulator of the anti-oxidative and detoxifying cellular response. Thus, a role in inflammatory diseases associated with the generation of large amounts of reactive oxygen species (ROS) seems obvious. In line with this, data obtained in cell culture experiments and preclinical settings have shown that Nrf2 is important in regulating target genes that are necessary to ensure cellular redox balance. Additionally, Nrf2 is involved in the induction of phase II drug metabolizing enzymes, which are important both in degrading and converting drugs into active forms, and into putative carcinogens. Therefore, Nrf2 has also been implicated in tumorigenesis. This must be kept in mind when new therapy approaches are planned for the treatment of sepsis. Therefore, this review highlights the function of Nrf2 in sepsis with a special focus on the translation of rodent-based results into sepsis patients in the intensive care unit (ICU).

Regulatory T cells (T_regs) are important mediators of immunological self-tolerance and homeostasis. Being cluster of differentiation 4⁺Forkhead box protein3⁺ (CD4⁺FOXP3⁺), these cells are a subset of CD4⁺ T lymphocytes and can originate from the thymus (tT_regs) or from the periphery (pT_regs). The malfunction of CD4⁺ T_regs is associated with autoimmune responses such as rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes (T1D), inflammatory bowel diseases (IBD), psoriasis, systemic lupus erythematosus (SLE), and transplant rejection. Recent evidence supports an opposed role in sepsis. Therefore, maintaining functional T_regs is considered as a therapy regimen to prevent autoimmunity and allograft rejection, whereas blocking T_reg differentiation might be favorable in sepsis patients. It has been shown that T_regs can be generated from conventional naïve T cells, called iT_regs, due to their induced differentiation. Moreover, T_regs can be effectively expanded in vitro based on blood-derived tT_regs. Taking into consideration that the suppressive role of T_regs has been mainly attributed to the expression and function of the transcription factor Foxp3, modulating its expression and binding to the promoter regions of target genes by altering the chromatin histone acetylation state may turn out beneficial. Hence, we discuss the role of histone deacetylation inhibitors as epigenetic modulators of T_regs in this review in detail.