Senescence determines the fate of activated rat pancreatic stellate cells.

In chronic pancreatitis (CP), persistent activation of pancreatic stellate cells (PSC) converts wound healing into a pathological process resulting in organ fibrosis. Here, we have analysed senescence as a novel mechanism involved in the termination of PSC activation and tissue repair. PSC senescence was first studied in vitro by establishing long-term cultures and by applying chemical triggers, using senescence-associated ß-Galactosidase (SA ß-Gal) as a surrogate marker. Subsequently, susceptibility of PSC to immune cell-mediated cytolysis was investigated employing cocultures. Using the model of dibutyltin dichloride-induced CP in rats, appearance of senescent cells was monitored by immunohistochemistry and immunofluorescence, and correlated with the progression of tissue damage and repair, immune cell infiltration and fibrosis. The results indicated that long-term culture and exposure of PSC to stressors (doxorubicin, H(2) O(2) and staurosporine) induced senescence. Senescent PSC highly expressed CDKN1A/p21, mdm2 and interleukin (IL)-6, but displayed low levels of α-smooth muscle actin. Senescence increased the susceptibility of PSC to cytolysis. In CP, the number of senescent cells correlated with the severity of inflammation and the extension of fibrosis. Areas staining positive for SA ß-Gal overlapped with regions of fibrosis and dense infiltrates of immune cells. Furthermore, a close physical proximity of immune cells and activated PSC was observed. We conclude that inflammation, PSC activation and cellular senescence are timely coupled processes which take place in the same microenvironment of the inflamed pancreas. Lymphocytes may play a dual-specific role in pancreatic fibrogenesis, triggering both the initiation of wound healing by activating PSC, and its completion by killing senescent stellate cells.

Forensic hydro-meteorological analysis of an extreme flash flood: The 2016-05-29 event in Braunsbach, SW Germany.

The flash-flood in Braunsbach in the north-eastern part of Baden-Wuerttemberg/Germany was a particularly strong and concise event which took place during the floods in southern Germany at the end of May/early June 2016. This article presents a detailed analysis of the hydro-meteorological forcing and the hydrological consequences of this event. A specific approach, the "forensic hydrological analysis" was followed in order to include and combine retrospectively a variety of data from different disciplines. Such an approach investigates the origins, mechanisms and course of such natural events if possible in a "near real time" mode, in order to follow the most recent traces of the event. The results show that it was a very rare rainfall event with extreme intensities which, in combination with catchment properties, led to extreme runoff plus severe geomorphological hazards, i.e. great debris flows, which together resulted in immense damage in this small rural town Braunsbach. It was definitely a record-breaking event and greatly exceeded existing design guidelines for extreme flood discharge for this region, i.e. by a factor of about 10. Being such a rare or even unique event, it is not reliably feasible to put it into a crisp probabilistic context. However, one can conclude that a return period clearly above 100years can be assigned for all event components: rainfall, peak discharge and sediment transport. Due to the complex and interacting processes, no single flood cause or reason for the very high damage can be identified, since only the interplay and the cascading characteristics of those led to such an event. The roles of different human activities on the origin and/or intensification of such an extreme event are finally discussed.