Critical Care of Hematopoietic Stem Cell Transplant Patients.

Life-threatening complications are frequent after hematopoietic stem cell transplant (HSCT), and optimum critical care is essential to ensuring good outcomes. The immunologic consequences of HSCT result in a markedly different host response to critical illness. Infection is the most common cause of critical illness but noninfectious complications are frequent. Respiratory failure or sepsis are the typical presentations but the sequelae of HSCT can affect nearly any organ system. Pattern recognition can facilitate anticipation and early intervention in post-HSCT critical illness. HSCT critical care is a multidisciplinary endeavor. Continued investigation and focus on process improvement will continue to improve outcomes.

Xanthine oxidoreductase is a critical mediator of cigarette smoke-induced endothelial cell DNA damage and apoptosis.

Cigarette smoke (CS) exposure is unquestionably the most frequent cause of emphysema in the United States. Accelerated pulmonary endothelial cell (EC) apoptosis is an early determinant of lung destruction in emphysema. One of the pathogenic causes of emphysema is an alveolar oxidant and antioxidant imbalance. The enzyme xanthine oxidoreductase (XOR) has been shown to be a source of reactive oxygen species (ROS) in a multitude of diseases (S. Sakao et al., FASEB J.21, 3640-3652; 2007). The contribution of XOR to CS-induced apoptosis is not well defined. Here we demonstrate that C57/bl6 mice exposed to CS have increased pulmonary XOR activity and protein levels compared to filtered-air-exposed controls. In addition, we demonstrate that primary pulmonary human lung microvascular endothelial cells exposed to cigarette smoke extract undergo increased rates of caspase-dependent apoptosis that are reliant on XOR activity, ROS production, and p53 function/expression. We also demonstrate that exogenous XOR is sufficient to increase p53 expression and induce apoptosis, suggesting that XOR is an upstream mediator of p53 in CS-induced EC apoptosis. Furthermore, we show that XOR activation results in DNA double-strand breaks that activate the enzyme ataxia telangiectasia mutated, which phosphorylates histone H2AX and upregulates p53. In conclusion, CS increases XOR expression, and the enzyme is both sufficient and necessary for p53 induction and CS-induced EC apoptosis.