Search PubMed⌕ Search

Biomedical subjects

Clifford S Deutschman

Publications and source records attributed to Clifford S Deutschman.

15 recordsLinked to original sources
PubMed2007

Cytokine response is lower after lung volume reduction through bilateral thoracoscopy versus sternotomy.

BACKGROUND: Lung volume reduction surgery performed through bilateral video-assisted thoracoscopy (BVATS) was associated in the National Emphysema Treatment Trial with a statistically significant reduction in intensive care unit days, failure to wean, hospital stay, and cost, and earlier recovery compared with median sternotomy. Studies comparing other minimally invasive techniques with "open" procedures, including pulmonary lobectomy, have demonstrated reduced serum proinflammatory mediators postoperatively. We measured these levels after lung volume reduction surgery through BVATS and sternotomy. METHODS: Serum cytokine levels were measured by radioimmunoassay in 9 consecutive, steroid-free patients undergoing sternotomy and lung volume reduction surgery and 6 undergoing BVATS and lung volume reduction surgery. The groups were not statistically different with respect to age, partial pressure of arterial carbon dioxide, percent forced expiratory volume in 1 second, percent residual volume, percent total lung capacity, diffusion capacity of the lung for carbon monoxide, 6-minute walk, or apical perfusion fraction. Proinflammatory interleukin 6 and interleukin 8 and antiinflammatory interleukin 10 were evaluated preoperatively and postoperatively on days 1, 4, and 5. Clinical data were prospectively collected. RESULTS: There were no major postoperative complications or deaths. Interleukin 6 levels were lower in the BVATS than the sternotomy group (p = 0.016 by repeated measures analysis of variance). Interleukin 8 levels were lower in the BVATS group at most postoperative time points, but there were no significant differences in interleukin 8 or interleukin 10 levels between the sternotomy and BVATS groups at any individual time point or by analysis of variance. CONCLUSIONS: Use of a BVATS approach to lung volume reduction surgery is associated with reduced postoperative release of proinflammatory cytokines compared with a sternotomy approach. This may account for the reduction in recovery time and some measures of postoperative morbidity seen with the BVATS approach.

Aged↗
PubMed2006

Sepsis-induced lung injury in rats increases alveolar epithelial vulnerability to stretch.

OBJECTIVE: Previous in vitro models have shown that cellular deformation causes dose-dependent injury and death in healthy rat alveolar epithelial cells (AECs). We compared the viability of AECs from septic rats with those from nonseptic rats after 1 hr of cyclic equibiaxial stretch. We hypothesized that sepsis would increase stretch-induced cell death. DESIGN: Laboratory investigation. SETTING: University research laboratory. SUBJECTS: Thirty-seven male Sprague-Dawley rats weighing 240-260 g. INTERVENTIONS: Anesthetized rats were subjected to cecal ligation and double puncture (2CLP) or sham laparotomy without cecal ligation or puncture (sham). After 24 or 48 hrs, AECs were isolated, seeded in custom wells, and maintained in culture for 48 hrs before study. AECs were stretched cyclically (15/min) to a 0%, 12%, 25%, or 37% change in surface area (DeltaSA) for 1 hr. Cell viability, phenotypic markers, and nuclear factor-kappaB intracellular localization were assessed using fluorescent immunocytochemistry. MEASUREMENTS AND MAIN RESULTS: Phase and fluorescent images were evaluated for all studies. Response to stretch was the same at 24 and 48 hrs after 2CLP. Relative to sham, 2CLP significantly increased cell death at 25 and 37% DeltaSA (p<.003, analysis of variance). Relative to sham, 2CLP did not alter expression of type I or type II phenotypic markers. Nuclear factor-kappaB within the nuclear compartment was observed after 2CLP in unstretched cells and after 1 hr of cyclic stretch at 37% DeltaSA. In sham, nuclear factor-kappaB within the nuclear compartment was seen only after stretch. CONCLUSIONS: AECs isolated from septic rats are more vulnerable to mechanical deformation injury than AECs from nonseptic animals.

Animals↗
PubMed2006

Sepsis-induced cholestasis, steatosis, hepatocellular injury, and impaired hepatocellular regeneration are enhanced in interleukin-6 -/- mice.

OBJECTIVE: Hepatic dysfunction is an important but poorly understood component of sepsis. In severe sepsis, liver dysfunction is characterized by cholestasis, steatosis, hepatocellular injury, impaired regeneration, a decreased response to the cytokine interleukin-6, and high mortality. To determine whether loss of interleukin-6 activity caused hepatic dysfunction and mortality, we induced sepsis in wild-type (interleukin-6 +/+) and interleukin-6 knockout (interleukin-6 -/-) mice. We hypothesized that sepsis in interleukin-6 -/- mice would increase cholestasis, steatosis, hepatocellular injury, and mortality and impair hepatocyte regeneration. DESIGN: Randomized prospective experimental study. SETTING: University medical laboratory. SUBJECTS: Male adolescent C57Bl6 interleukin-6 +/+ and interleukin-6 -/- mice. INTERVENTIONS: Mild sepsis was induced using cecal ligation and single puncture (CLP). Severe, lethal sepsis was induced using cecal ligation and double puncture (2CLP). Some mice received recombinant human interleukin-6 at the time of CLP/2CLP. All animals were fluid resuscitated at the time of surgery and every 24 hrs thereafter. In survival cohorts, mortality at 16, 24, 48, and 72 hrs was recorded. In separate cohorts, surviving animals were killed at 24 and 48 hrs, and liver tissue was harvested. A separate cohort of mice received bromodeoxyuridine for detection of regeneration. MEASUREMENTS AND MAIN RESULTS: 2CLP was 100% fatal within the first 12 hrs in interleukin-6 -/- mice. Mortality from 2CLP in interleukin-6 +/+ mice before 24 hrs was nil but was 90% by 72 hrs. At 72 hrs, CLP was 40% fatal in interleukin-6 +/+ mice but 90% in interleukin-6 -/- mice. CLP induced cholestasis, steatosis, and hepatocellular injury in interleukin-6 -/-, but not interleukin-6 +/+, mice. Regeneration was absent following CLP in interleukin-6 -/- animals but occurred in interleukin-6 +/+ mice. Early administration of recombinant human interleukin-6 did not reverse abnormalities in interleukin-6 -/- mice. CONCLUSIONS: The absence of interleukin-6 is an important determinant of hepatic dysfunction and mortality in sepsis.

Animals↗
PubMed2006

The inflammatory response to surgery and trauma.

PURPOSE OF REVIEW: The inflammatory or stress response to injury has evolved to ensure survival. This review will examine this response in otherwise healthy patients. Additionally, the impact of several common comorbid conditions on the inflammatory response will be considered. What will become evident is that the stress response may be exaggerated in some conditions and suppressed in others. Rapid identification of both an abnormal response and its cause will allow clinicians to maximize a patient's healing potential. RECENT FINDINGS: Recent work has shown that an altered inflammatory response has marked effects on both immune competence and the endocrine system. Investigations are ongoing to delineate the mechanism of lymphocyte dysfunction. With regard to critical care endocrinopathies, the effects of insulin and hyperglycemia on inflammation and wound healing are being investigated. SUMMARY: An understanding of the stress response will aid the clinician in preparing for expected responses, recognizing and perhaps correcting deviations from the norm and accounting for potential complications that arise in the face of preexisting disease. Deviations from the normal time course may represent the effects of preexisting medical illness, treatment or postoperative/injury complications.

Humans↗
PubMed2005

Chronic hypoxemia increases myocardial cytochrome oxidase.

OBJECTIVE: Cyanotic patients have potentially decreased tissue oxygen tension. Cytochrome oxidase catalyzes the reduction of oxygen and is integral to adenosine triphosphate production. Cytochrome oxidase subunit I, the active site, is encoded by mitochondrial DNA. Using a newborn swine model of chronic hypoxemia, we evaluated ventricular cytochrome oxidase subunit I mRNA and protein expression and assessed cytochrome oxidase activity. METHODS: Thirty-two newborn piglets underwent thoracotomy and placement of a pulmonary artery-to-left atrium shunt or sham operation. Two weeks later, partial pressure of arterial oxygen, hematocrit, and left ventricular shortening fraction values were compared with baseline values. Northern blot hybridization and protein immunoblotting for ventricular cytochrome oxidase subunit I were performed. Cytochrome oxidase kinetic activity was measured. Heme a,a3 content and turnover number were determined. Significance was assessed with a t test. RESULTS: Baseline partial pressure of arterial oxygen and hematocrit values were similar. Hypoxemic piglets had a lower partial pressure of arterial oxygen of 38 +/- 10 mm Hg (P < .001) and higher hematocrit value of 31.4% +/- 2.9% (P < .001) compared with a partial pressure of arterial oxygen of 140 +/- 47 mm Hg and hematocrit value of 24.6% +/- 3.9% after the sham operation. Baseline and postprocedure left ventricular shortening fraction were similar within and between groups. Chronic hypoxemia increased right ventricular and left ventricular cytochrome oxidase I mRNA and protein by more than 1.4-fold. Cytochrome oxidase activity increased significantly in hypoxemia by 2.5-fold compared with that seen after the sham operation. Heme a,a3 content and turnover number increased by 1.5-fold during hypoxemia. CONCLUSIONS: Chronic hypoxemia increases cytochrome oxidase I message, protein expression, and activity. The increase in kinetics was due to increased enzyme content and catalytic activity. This is a possible adaptive mechanism that might preserve organ function during chronic hypoxemia.

Animals↗
PubMed2005

Transcription.

Explore the source record for details and available documents.

Genetic Techniques↗
PubMed2005

Evidence of myocardial hibernation in the septic heart.

OBJECTIVE: Myocardial hibernation is an adaptive response to ischemia and hypoxia. Hibernating cardiomyocytes are reversibly hypocontractile and demonstrate characteristic metabolic and ultrastructural changes. These include a switch in primary substrate utilization from fatty acids to glucose, up-regulation of the myocardial specific glucose transporters (GLUT1 and GLUT4), and glycogen deposition within and between cardiomyocytes. We hypothesized that myocardial hibernation may underlie sepsis-associated myocardial depression. DESIGN: Prospective observational study aimed at identifying the characteristic changes of hibernation in the septic heart. SETTING: University hospital-based laboratory. SUBJECTS: Forty-three C57Bl6 male mice. INTERVENTIONS: Mice underwent cecal ligation and double puncture, sham operation, or no operation and were evaluated 48 hrs after the procedure. MEASUREMENTS AND MAIN RESULTS: Using novel, clinically relevant technology such as magnetic resonance imaging, positron emission tomography, and single photon emission computed tomography imaging, we found septic mice to have diminished cardiac performance, increased myocardial glucose uptake, increased steady-state levels of myocardial GLUT4, and increased deposits of glycogen, recapitulating the changes during hibernation. Importantly, these changes occurred in the setting of preserved arterial oxygen tension and myocardial perfusion. CONCLUSIONS: Sepsis-associated cardiac dysfunction may reflect hibernation. Furthermore, such down-regulation of cellular function may underlie sepsis-induced dysfunction in other organ systems.

Animals↗
PubMed2004

Competitive and noncompetitive inhibition of myocardial cytochrome C oxidase in sepsis.

Sepsis is the most common cause of death in intensive care units worldwide. The basic pathophysiologic defect in sepsis, causing functional abnormalities in many organ systems, remains elusive. One potential cause is disruption of oxidative phosphorylation in mitochondria. Here, we report that oxidation of cytochrome c by myocardial cytochrome c oxidase, the terminal oxidase in the electron transport chain, is competitively inhibited early in experimental sepsis (cecal ligation with single or double 23-gauge puncture) in mice. In severe sepsis (cecal ligation and double puncture, 75% mortality at 48 h), inhibition becomes noncompetitive by 48 h. The development of noncompetitive inhibition is associated with a decrease in heme a,a3 content, which is the key active site in the functional subunit (I) and catalyzes the reduction of molecular oxygen. In addition, there are persistently decreased steady-state levels of subunit I mRNA and protein after cecal ligation and double puncture. Both loss of heme and loss of subunit I could explain the observed irreversible inhibition of cytochrome c oxidase. Noncompetitive inhibition of cytochrome c oxidase may interrupt oxidative phosphorylation, leading to sepsis-associated cardiac depression. Importantly, this abnormality may underlie sepsis-associated dysfunction in other organ systems.

Animals↗
PubMed2003

Transcription factors C/EBP-alpha and HNF-1alpha are associated with decreased expression of liver-specific genes in sepsis.

Previous studies have demonstrated sepsis-specific changes in the transcription of key hepatic genes. However, the role of hepatic transcription factors in sepsis-associated organ dysfunction has not been well established. We hypothesize that the binding activities of C/EBPalpha and beta, HNF-1alpha, and HNF-3 transiently decrease during mild sepsis but persistently decrease after fulminant sepsis, and that the decrease in this binding activity correlates in time and severity with previously described decreases in the transcription of key hepatic genes. Male C57/BL6 mice had nonlethal sepsis induced by cecal ligation and single puncture (CLP) and fulminant sepsis via cecal ligation and double puncture (2CLP). Sham-operated and unoperated animals served as controls. Transcription factor binding activity was assessed with electrophoretic mobility shift assays. C/EBP-a and HNF-1alpha binding activity decreased transiently after CLP and persistently after 2CLP. Binding activity of both C/EBP-beta and HNF-3 were unchanged. The decrease in C/EBP-a and HNF-1alpha binding activities correlated in time and magnitude with the decreased hepatic gene transcription previously observed in sepsis. Furthermore, the loss of activity after 2CLP correlated in time with outcome. Sepsis decreases DNA binding activities of C/EBPalpha and HNF-1alpha, two key hepatocyte transcription factors, in a time course consistent with down-regulation of their target hepatic genes. Therefore, alterations in transcription factor binding are likely important in the transcriptional modulation that is characteristic of hepatic dysfunction in sepsis.

Animals↗
PubMed2002

Adenoviral transfer of HSP-70 into pulmonary epithelium ameliorates experimental acute respiratory distress syndrome.

The acute respiratory distress syndrome (ARDS) provokes three pathologic processes: unchecked inflammation, interstitial/alveolar protein accumulation, and destruction of pulmonary epithelial cells. The highly conserved heat shock protein HSP-70 can limit all three responses but is not appropriately expressed in the lungs after cecal ligation and double puncture (2CLP), a clinically relevant model of ARDS. We hypothesize that restoring expression of HSP-70 using adenovirus-mediated gene therapy will limit pulmonary pathology following 2CLP. We administered a vector containing the porcine HSP-70 cDNA driven by a CMV promoter (AdHSP) into the lungs of rats subjected to 2CLP or sham operation. Administration of AdHSP after either sham operation or 2CLP increased HSP-70 protein expression in lung tissue, as determined by immunohistochemistry and Western blot hybridization. Administration of AdHSP significantly attenuated interstitial and alveolar edema and protein exudation and dramatically decreased neutrophil accumulation, relative to a control adenovirus. CLP-associated mortality at 48 hours was reduced by half. Modulation of HSP-70 production reduces pathologic changes and may improve outcome in experimental ARDS.

Adenoviridae↗