Bruton's tyrosine kinase inhibition attenuates disease progression by reducing renal immune cell invasion in mice with hemolytic-uremic syndrome

Hemolytic-uremic syndrome (HUS) can occur as a complication of an infection with Shiga-toxin (Stx)-producing Escherichia coli . Patients typically present with acute kidney injury, microangiopathic hemolytic anemia and thrombocytopenia. There is evidence that Stx-induced renal damage propagates a pro-inflammatory response. To date, therapy is limited to organ-supportive strategies. Bruton’s tyrosine kinase (BTK) plays a pivotal role in recruitment and function of immune cells and its inhibition was recently shown to improve renal function in experimental sepsis and lupus nephritis. We hypothesized that attenuating the evoked immune response by BTK-inhibitors (BTKi) ameliorates outcome in HUS. We investigated the effect of daily oral administration of the BTKi ibrutinib (30 mg/kg) and acalabrutinib (3 mg/kg) in mice with Stx-induced HUS at day 7. After BTKi administration, we observed attenuated disease progression in mice with HUS. These findings were associated with less BTK and downstream phospholipase-C-gamma-2 activation in the spleen and, subsequently, a reduced renal invasion of BTK-positive cells including neutrophils. Only ibrutinib treatment diminished renal invasion of macrophages, improved acute kidney injury and dysfunction (plasma levels of NGAL and urea) and reduced hemolysis (plasma levels of bilirubin and LDH activity). In conclusion, we report here for the first time that BTK inhibition attenuates the course of disease in murine HUS. We suggest that the observed reduction of renal immune cell invasion contributes – at least in part – to this effect. Further translational studies are needed to evaluate BTK as a potential target for HUS therapy to overcome currently limited treatment options

Traffic-related environmental risk factors and their impact on oxidative stress and cardiovascular health

The adverse effects of the environment on health are increasingly recognized. The WHO estimates that noise accounts for 1 million annually lost healthy life years in Western Europe due to increased incidence of hypertension, heart failure, myocardial infarction, and stroke. An even more severe health impact was reported for air pollution (e.g., PM2.5) accounting for up to 800,000 annual excess deaths in Europe. Adverse effects of air pollution are mechanistically better characterized, but there is still a great need to understand the pathophysiology of air pollution-induced cardiovascular disease, especially the potential synergistic effects together with noise. With the present book chapter, we discuss the most recent data on noise/ air pollution-induced stress responses that increase blood pressure, heart rate, stress hormone levels, and oxidative stress leading to vascular dysfunction and worsening of cardiovascular prognosis. The impact of these environmental risk factors on redox signaling and oxidative stress is discussed in detail