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Neuronal nitric oxide synthase is critically involved in the pathogenesis of acute lung injury resulting from combined burn and smoke inhalation injury. We hypothesized that 7-nitroindazole, a selective neuronal nitric oxide synthase inhibitor, blocks central molecular mechanisms involved in the pathophysiology of this double-hit insult. Twenty-five adult ewes were surgically prepared and randomly allocated to 1) an uninjured, untreated sham group (n = 7), 2) an injured control group with no treatment (n = 7), 3) an injury group treated with 7-nitroindazole from 1-h postinjury to the remainder of the 24-h study period (n = 7), or 4) a sham-operated group subjected only to 7-nitroindazole to judge the effects in health. The combination injury was associated with twofold increased activity of neuronal nitric oxide synthase and oxidative/nitrosative stress, as indicated by significant increases in plasma nitrate/nitrite concentrations, 3-nitrotyrosine (an indicator of peroxynitrite formation), and malondialdehyde lung tissue content. The presence of systemic inflammation was evidenced by twofold, sixfold, and threefold increases in poly(ADP-ribose) polymerase, IL-8, and myeloperoxidase lung tissue concentrations, respectively (each P < 0.05 vs. sham). These molecular changes were linked to tissue damage, airway obstruction, and pulmonary shunting with deteriorated gas exchange. 7-Nitroindazole blocked, or at least attenuated, all these pathological changes. Our findings suggest 1) that nitric oxide formation derived from increased neuronal nitric oxide synthase activity represents a pivotal reactive agent in the pathophysiology of combined burn and smoke inhalation injury and 2) that selective neuronal nitric oxide synthase inhibition represents a goal-directed approach to attenuate the degree of injury. pathogenesis; acute lung injury doi:10.1152/ajplung.00147.2009.

Byline: Marc O. Maybauer (1,3), Dirk M. Maybauer (2,3), John F. Fraser (4), Lillian D. Traber (2), Martin Westphal (2,5), Robert A. Cox (2), Ruksana Huda (2), Yoshimitsu Y. Nakano (2), Perenlei Enkhbaatar (2), Hal K. Hawkins (2), David N. Herndon (2), Daniel L. Traber (2) Keywords: Airway obstruction; Acute lung injury; Acute respiratory distress syndrome; Nitric oxide; 3-Nitrotyrosine; Sepsis Abstract: Objective To investigate ceftazidime in acute lung injury (ALI) and sepsis. Design and setting Prospective, randomized, controlled animal study in an investigational ICU at a university hospital. Interventions Eighteen female Merino sheep were prepared for chronic study and subjected to smoke inhalation and septic challenge according to an established protocol. Measurements and results Whereas global hemodynamics and oxygenation remained stable in sham animals (no injury, no treatment), the injury contributed to a hypotensive-hyperdynamic circulation in the control group (smoke inhalation and sepsis, no treatment), as indicated by a significant increase in cardiac index) and heart rate and a drop in mean arterial pressure. Treatment with ceftazidime (smoke inhalation and sepsis, treatment group) stabilized cardiac index and heart rate and attenuated the decrease in mean arterial pressure. The deterioration in PaO.sub.2/FiO.sub.2 ratio and pulmonary shunt fraction (Qs/Qt) was significantly delayed and blunted by ceftazidime. At 24a-h after injury a significant increase in airway obstruction scores of bronchi and bronchioles in both injured groups was observed. Ceftazidime significantly reduced airway obstruction vs. control animals. Whereas plasma nitrate/nitrite levels increased similarly in the two injured groups, lung 3-nitrotyrosine content remained at the baseline level in the ceftazidime group. Conclusions In ovine lung injury ceftazidime improves global hemodynamics and oxygenation not only by bacterial clearance but also via reduction in toxic nitrogen species such as 3-nitrotyrosine. Therefore ceftazidime appears as a clinically relevant adjunct in the common setting of sepsis-associated lung injury. Author Affiliation: (1) Investigational Intensive Care Unit, University of Texas Medical Branch and Shriners Burns Hospital, 301 University Blvd., 77555-0833, Galveston, TX, USA (2) Departments of Anesthesiology, Pathology, and Surgery, Investigational Intensive Care Unit, University of Texas Medical Branch and Shriners Burns Hospital for Children at Galveston, Tex., USA (3) Department of Anesthesiology and Intensive Care, Sektion Anasthesiologische Pathophysiologie und Verfahrensentwicklung, University of Ulm, Steinhovelstrasse 9, 89075, Ulm, Germany (4) Royal Children's Hospital Burns Research Group and Prince Charles Hospital, University of Queensland, Brisbane, Australia (5) Department of Anesthesiology and Intensive Care Medicine, University of Munster, Munster, Germany Article History: Registration Date: 10/04/2007 Received Date: 02/08/2006 Accepted Date: 06/04/2007 Online Date: 15/05/2007 Article note: M.O.M. and D.M.M. contributed equally to this study and manuscript. An erratum to this article can be found at http://dx.doi.org/10.1007/s00134-007-0752-6

We investigated the role of the nuclear enzyme poly (ADP ribose) synthetase (PARS) in the pathogenesis of combined burn and smoke inhalation (burn/smoke) injury in an ovine model. Eighteen sheep were operatively prepared for chronic study. PARS inhibition was achieved by treatment with a novel and selective PARS inhibitor INO-1001. The PARS inhibitor attenuated 1) lung edema formation, 2) deterioration of gas exchange, 3) changes in airway blood flow, 4) changes in airway pressure, 5) lung histological injury, and 6) systemic vascular leakage. Lipid oxidation and plasma nitrite/nitrate (stable breakdown products of nitric oxide) levels were suppressed with the use of INO-1001. We conclude that PARS inhibition attenuates various aspects of the pathophysiological response in a clinically relevant experimental model of burn/smoke inhalation injury. acute respiratory distress syndrome; lung lymphatic; nitric oxide

Genetically altered mice and unique experimental procedures involving coronary occlusion were developed for the study of the inflammatory reactions following myocardial ischemia-reperfusion. The procedures allow the assessment of cardiac function, area at risk and infarct size. These procedures combined with transgenic mice overexpressing or deficient in certain genes would allow the assessment of the role of specific gene products in the pathophysiology of inflammation and myocardial injury following ischemia-reperfusion.

The absence of intercellular adhesion molecule 1 (ICAM-1) or CD54, a cell adhesion molecule resembling immunoglobulin, in mutant mice results in the dysfunction of inflammatory and immune responses. Homologous recombination facilitates mutation in the ICAM-1 gene. Chemical peritonitis in such mice evokes in response characterized by irregular and disordered neutrophil efflux and a decline in contact hypersensitivity to 2,4-dinitrofluorobenzene. Cell surface expression of mutant transcription is characteristically absent during a quantitative analysis of ICAM-1 expression.

Thermal injury has been shown to alter gut epithelium and heart myocyte homeostasis by inducing programmed cell death. The effect of thermal injury on hepatocyte apoptosis and proliferation, however, has not been established. The purpose of this study was to determine whether a large thermal injury increases liver cell apoptosis and proliferation and whether these changes were associated with alterations in hepatic nuclear factor [Kappa]B (NF-[Kappa]B) expression and changes in liver enzymes and amount of protein. Sprague-Dawley rats received a 40% total body surface area scald burn or sham burn. Rats were killed and livers were harvested at 1, 2, 5, and 7 days after burn. Liver cell apoptosis was determined by terminal deoxyuridine nick end labeling (TUNEL) assay and cell proliferation by immunohistochemistry for proliferating cell nuclear antigen. Hepatic NF-[Kappa]B expression was determined by Western blot, and total hepatic protein content was determined by protein assay. Protein concentration decreased after burn compared with sham controls (P [is less than] 0.05). Liver cell apoptosis, proliferation, and NF-[Kappa]B expression in hepatocytes increased in burned rats compared with controls (P [is less than] 0.05). It was concluded that thermal injury induces hepatic cell apoptosis and proliferation associated with an increase in hepatic NF-[Kappa]B expression and a decrease in hepatic protein concentration. thermal injury; hepatic cells.

* The expression of myelomonocytic-associated antigens in anaplastic large cell lymphomas (ALCLs), particularly those presenting in extranodal sites, can make their distinction from extramedullary myeloid cell tumors (EMCTs) or histiocytic tumors problematic. Yet, this distinction is clinically significant because of its therapeutic and prognostic implications. Herein, we describe a case of extranodal anaplastic lymphoma kinase-positive CD30-positive ALCL of T-cell origin in a 12-year-old boy, which was initially called an EMCT because of the expression of CD13 and HLA-DR detected by flow cytometry and the absence of other T-cell-related surface markers. However, the detection of cytoplasmic CD3 by flow cytometry prompted further studies. The tumor was composed of large cells with abundant slightly eosinophilic vacuolated cytoplasm and ovoid or reniform nuclei with a few small nucleoli. Using immunohistochemistry, the tumor was positive for CD45, CD30, CD45RO, and CD43 with a strong cytoplasmic and nuclear anaplastic lymphoma kinase stain. The tumor cells showed a T-cell clonal genotype. Electron microscopy revealed no ultrastructural features of myelomonocytic or histiocytic origin. The patient responded well to the chemotherapy and was in complete remission for 10 months at the time of submission of this manuscript. Review of the literature showed inconsistencies regarding the diagnosis, nomenclature, and, therefore, treatment and prognosis of these tumors. In addition, the CD13 expression in ALCL raises some histogenetic questions and may indicate origin from a pluripotent stem cell, misprogramming during malignant transformation, or a microenvironmental effect on lymphoid cell expression of surface antigens. Therefore, ALCL should be considered in the differential diagnosis of EMCTs or histiocytic tumors, particularly when surface marker lineage assignment is ambiguous. (Arch Pathol Lab Med. 2000;124:1804-1808), A Case Report and Review of the Literature Anaplastic large cell lymphomas (ALCLs) are characterized by a pleomorphic appearance, sinus growth pattern, and CD30 positivity. These neoplasms are heterogeneous in [...]

Byline: Marc O. Maybauer (1,3), Dirk M. Maybauer (2,3), John F. Fraser (4), Lillian D. Traber (2), Martin Westphal (2,5), Robert A. Cox (2), Ruksana Huda (2), Yoshimitsu Y. Nakano (2), Perenlei Enkhbaatar (2), Hal K. Hawkins (2), David N. Herndon (2), Daniel L. Traber (2) Author Affiliation: (1) Investigational Intensive Care Unit, University of Texas Medical Branch and Shriners Burns Hospital, 301 University Blvd., 77555-0833, Galveston, TX, USA (2) Departments of Anesthesiology, Pathology, and Surgery, Investigational Intensive Care Unit, University of Texas Medical Branch and Shriners Burns Hospital for Children at Galveston, Tex., USA (3) Department of Anesthesiology and Intensive Care, Sektion Anasthesiologische Pathophysiologie und Verfahrensentwicklung, University of Ulm, Steinhovelstrasse 9, 89075, Ulm, Germany (4) Royal Children's Hospital Burns Research Group and Prince Charles Hospital, University of Queensland, Brisbane, Australia (5) Department of Anesthesiology and Intensive Care Medicine, University of Munster, Munster, Germany Article History: Registration Date: 30/05/2007 Online Date: 16/06/2007 Article note: The online version of the original can be found at http://dx.doi.org/10.1007/s00134-007-0658-3.