Rapid response team responses.
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Critical Care↗
Biomedical subjects
Christopher K Cook
Publications and source records attributed to Christopher K Cook.
Laminar flow induction of antioxidant response element-mediated genes in endothelial cells. A novel anti-inflammatory mechanism.
Atherosclerotic lesions preferentially develop in areas of the vasculature exposed to nonlaminar blood flow and low fluid shear stress, whereas laminar flow and high fluid shear stress are athero-protective. We have identified a set of genes including NAD(P)H:quinone oxidoreductase-1 (NQO1), heme oxygenase-1 (HO-1), ferritin (heavy and light chains), microsomal epoxide hydrolase, glutathione S-transferase, and gamma-glutamylcysteine synthase, whose expression is induced by exposure to prolonged physiological levels of steady laminar flow (shear stress = 20 dyn/cm(2)) in endothelial cells (EC). These genes contain an antioxidant response element (ARE) or ARE-like transcriptional regulatory sequence in their promoters and generally function to protect cells against oxidant stress. We demonstrate that exposure of EC to laminar flow activates ARE-mediated transcriptional activity. Mutation of the ARE from either the NQO1 or HO-1 promoter abolished laminar flow-induced NQO1 and HO-1 transcriptional activation. Expression of antisense Nrf2 (a transcriptional factor for ARE), a dominant negative Nrf2, or the cytoplasmic inhibitor of Nrf2 (Keap1/INrf2) inhibited laminar flow-induced NQO1 promoter activation in EC. In addition, expression of NQO1 or Nrf2 inhibited tumor necrosis factor-alpha-induced activation of VCAM-1 (vascular cell adhesion molecule-1) gene expression in EC. These data define the ARE as a novel endothelial shear stress response element. Furthermore, laminar flow activation of antioxidant genes via an ARE-dependent transcriptional mechanism may represent a novel athero-protective and anti-inflammatory mechanism in the vasculature.
Antioxidants↗
Mechanical ventilation in the management of acute respiratory distress syndrome.
The occurrence of acute respiratory distress syndrome (ARDS), is now common in intensive care units throughout the world. The diagnosis of ARDS is based on a definition that includes bilateral pulmonary infiltrates on chest radiographs, impaired oxygenation, and the absence of clinical evidence of elevated left atrial pressure. ARDS is the clinical result of a group of diverse processes, which range from physical or chemical injury, to extensive activation of innate inflammatory response. All these processes damage the integrity of the alveolar-capillary barrier causing increased alveolar-capillary permeability and an influx of protein-rich fluid into the alveolar space. This alveolar flooding results in hypoxemia, inactivated surfactant, intrapulmonary shunt, and impaired alveolar ventilation. The treatment of acute respiratory distress syndrome is largely supportive in nature, keeping patients alive while allowing their lungs to heal, and minimizing further pulmonary insult. In 1994 the National Heart, Lung, and Blood Institute (NHLBI) established the ARDS Network for the conduct of clinical trials. This is a network, supported by the National Institutes of Health, that provided the infrastructure for well-designed, multicenter, randomized trials of therapies for ARDS. The first study from this group in 2001 produced landmark data demonstrating mortality improvements in ARDS with particular mechanical ventilation strategies. Specifically, low tidal volume mechanical ventilation was demonstrated to reduce mortality by 22%. Other strategies such as high positive end expiratory pressure and prone positioning have not been shown to reduce mortality. Clinicians who are involved in the care of patients with ARDS should have a basic understanding of mechanical ventilation and the evidence guiding the mechanical ventilation strategies of these patients. Until further evidence is published, providers should adopt the use of a volume and pressure limited approach to mechanical ventilation.
High-Frequency Ventilation↗