Animal Models

Hypercapnic acidosis has been previously reported to reduce acute lung injury in a model of in vivo ischemia-reperfusion and ventilation-induced lung injury. Laffey and coworkers reported that institution of hypercapnic acidosis with 5% CO₂ given before endotoxin-induced lung injury in rats reduced lung injury. There was less severe arterial hypoxemia, improved lung compliance, and reduced alveolar neutrophil infiltration. The hypercapnic acidosis was also associated with an attenuated increase in the higher oxides of nitrogen nitrosothiols in the lung tissue and epithelial lining fluid. Several limitations, as pointed out by the authors, need to be emphasized. Hypercapnia is ineffective when buffered to normal pH, and the studies were done in endotoxin-, not bacterial-induced, lung injury. In addition, the potential efficacy and safety of hypercapnic acidosis when used over longer time periods, particularly in a clinical setting, is unknown. Also, there were no dose-dependent data provided in this study.

To investigate the impact of increased intraabdominal pressure on respiration and hemodynamics, Quintel and coworkers measured mean pulmonary artery pressure and the pressure–volume curves of the total respiratory system, lung, and chest wall with or without pneumoperitonium in pigs. Using computed tomography, they found that the amount of edema increased by 30 ± 24% (455 ± 80 g) in the oleic acid–injured lung without pneumoperitonium, whereas the increase was 103 ± 37% (905 ± 134 g) in the presence of pneumoperitonium. The authors concluded that increased intraabdominal pressure exacerbates the amount of edema in oleic acid–induced lung injury.

It is unknown which of the three isoforms of inducible nitric oxide synthase contributes to the acute lung injury that results with burns and smoke inhalation. In control group of sheep, Enkhbaatar and coworkers found that third-degree burns involving 40% of the body surface plus insufflation of cotton smoke (48 breaths of less than 40°C) induced multiple features of ARDS. The abnormalities were accompanied by large increases in tracheal blood flow and increased plasma levels of nitrate/nitrite. A second group of sheep received a constant infusion of a highly selective inhibitor of inducible nitric oxide synthase (BBS-2), commencing 1 hour after injury. This inhibitor caused attenuation of all aspects of the pulmonary pathology, and lessened the increase in tracheal blood flow and plasma levels of nitrate/nitrite. The authors conclude that inducible nitric oxide synthase is a key mediator of the ARDS that results from burn and smoke inhalation injury in sheep.

Rocco and coworkers studied the effect of low-dose glucocorticoids on the lung injury caused by intraperitoneal administration of paraquat in rats. Both 10 and 25 mg/kg of paraquat induced increases in lung resistive, viscoelastic, and static elastance pressures on the first day after exposure. Hysterestivity was increased only with a paraquat dose of 25 mg/kg. Administration of methylprednisolone at either 1 or 6 hours produced attenuation of mechanical changes after 25 mg/kg of paraquat, but had no effect on changes induced by 10 mg/kg of paraquat. Collagen and elastic fibers increased in a dose-dependent fashion. Methylprednisolone prevented the increase in collagen and avoided elastogenesis. The authors conclude that methylprednisolone prevents the abnormal respiratory mechanics associated with mild lung injury caused by paraquat and minimizes the changes in tissue impedance and the extracellular matrix associated with severe lung injury caused by paraquat.

The hydrophobic surfactant protein C binds to lipopolysaccharide (which is found in airborne particles) and one of its cellular receptors, CD14. Augusto and coworkers investigated the influence of surfactant protein C on the responses of immunocompetent cells to lipopolysaccharide. When associated with vesicles of dipalmitoylphosphatidylcholine, surfactant protein C inhibited the mitogenic effect of lipopolysaccharide to a macrophage cell line (RAW 264.7). Under similar conditions, surfactant protein C inhibited the mitogenic effect of lipopolysaccharide on mouse splenocytes, inhibited the lipopolysaccharide-induced production of tumor necrosis factor- ${alpha}$ by peritoneal and alveolar macrophages, and of nitric oxide by the macrophage cell line. In contrast, surfactant protein C did not affect production of tumor necrosis factor- ${alpha}$ induced by a lipopeptide or production of nitric oxide induced by picolinic acid. The lipopolysaccharide-binding capacity of surfactant protein C was resistant to peroxynitrite (a known mediator of acute lung injury formed by the reaction of nitric oxide with superoxide anions). The authors conclude that surfactant protein C resists degradation under inflammatory conditions and traps lipopolysaccharide, preventing it from inducing the production of noxious mediators in alveolar cells.

Many genes elicited by bacteria in the lungs are regulated by ${kappa}$ B sites in DNA, which bind nuclear factor- ${kappa}$ B proteins. Mizgerd and coworkers determined whether the p50 subunit of nuclear factor- ${kappa}$ B limits the expression of ${kappa}$ B-associated genes and prevents excessive inflammation and injury. During pneumonia caused by Escherichia coli, gene-targeted deficiency of p50 caused increased mortality, but it did not alter bacterial clearance from mouse lungs. Deficiency of p50 caused increased expression of proinflammatory cytokines. The dysregulation produced aggravation of inflammation (increased neutrophil recruitment), pulmonary edema, worse gas exchange, and leak of protein and bacteria from the lungs with consequent bacteremia and multiple organ failure. The authors conclude that the endogenous p50 subunit of nuclear factor- ${kappa}$ B limits the inflammatory injury that occurs during pneumonia.

Citations 1-5 of 5 total displayed.

An Increase of Abdominal Pressure Increases Pulmonary Edema in Oleic Acid–induced Lung Injury

Michael Quintel, Paolo Pelosi, Pietro Caironi, Jurgen Peter Meinhardt, Thomas Luecke, Peter Herrmann, Paolo Taccone, Christian Rylander, Franco Valenza, Eleonora Carlesso, and Luciano Gattinoni
Am. J. Respir. Crit. Care Med. 169: 534 -541. First published online as doi:10.1164/rccm.200209-1060OC [Abstract] [Full text]

Hypercapnic Acidosis Attenuates Endotoxin-induced Acute Lung Injury

John G. Laffey, Dave Honan, Natalie Hopkins, Jean-Marc Hyvelin, John F. Boylan, and Paul McLoughlin
Am. J. Respir. Crit. Care Med. 169: 46 -56. First published online as doi:10.1164/rccm.200205-394OC [Abstract] [Full text]

Effect of Corticosteroid on Lung Parenchyma Remodeling at an Early Phase of Acute Lung Injury

Patricia R. M. Rocco, Alba B. Souza, Debora S. Faffe, Caroline P. Pássaro, Flávia B. Santos, Elnara M. Negri, Januário G. M. Lima, Renata S. Contador, Vera L. Capelozzi, and Walter A. Zin
Am. J. Respir. Crit. Care Med. 168: 677 -684. First published online as doi:10.1164/rccm.200302-256OC [Abstract] [Full text]

Cellular Antiendotoxin Activities of Lung Surfactant Protein C in Lipid Vesicles

Luis A. Augusto, Monique Synguelakis, Quentin Espinassous, Michel Lepoivre, Jan Johansson, and Richard Chaby
Am. J. Respir. Crit. Care Med. 168: 335 -341. First published online as doi:10.1164/rccm.200212-1440OC [Abstract] [Full text]

The Inducible Nitric Oxide Synthase Inhibitor BBS-2 Prevents Acute Lung Injury in Sheep after Burn and Smoke Inhalation Injury

Perenlei Enkhbaatar, Kazunori Murakami, Katsumi Shimoda, Akio Mizutani, Lillian Traber, Gary B. Phillips, John F. Parkinson, Robert Cox, Hal Hawkins, David Herndon, and Daniel Traber
Am. J. Respir. Crit. Care Med. 167: 1021-1026. [Abstract] [Full text]

Year in Review Home