Cellular and Molecular Mechanisms

To examine the putative role of high-mobility group box (HMGB) protein in the pathogenesis of acute lung injury, Ueno and coworkers analyzed data from both humans with sepsis and a mouse model. Observations were made in 21 patients with sepsis with acute lung injury and 15 patients with normal lung function, and in a mouse model, 24 hours after intratracheal instillation of LPS. The concentrations of HMGB1 were increased in plasma and lung epithelial lining fluid of patients with acute lung injury and mice instilled with LPS. LPS-induced acute lung injury was mitigated by anti-HMGB1 antibody. Although this protein was not detected in the plasma of control human subjects or mice, the concentrations of HMGB1 in lung epithelial lining fluid or in BAL fluid were unexpectedly high. The nuclear expression of HMGB1 was apparent in epithelial cells surrounding terminal bronchioles in normal mice, whereas its nuclear and cytoplasmic expression was observed in alveolar macrophages in LPS-instilled mice. Lung instillation of HMGB2 did not cause as much inflammation as HMGB1. The authors concluded that extracellular HMGB1 may play a key role in the pathogenesis of clinical and experimental acute lung injury. They added that its expression in normal airways is noteworthy, which suggests that it also plays a physiologic role in the lung.

Sphingosine 1-phosphate produces endothelial cell barrier enhancement in several experimental models. Peng and colleagues reported that sphingosine 1-phosphate infusion produced a rapid reduction in lung weight (> 50%) in isolated, perfused mouse lungs. Also, sphingosine 1-phosphate reduced endotoxin-induced lung vascular permeability and inflammation at both 6 and 24 hours. There was also a reduced extravasation of albumin and myeloperoxidase in renal tissues of the sphingosine 1-phosphate–treated mice that had been given endotoxin. Thus, sphingosine 1-phosphate is a promising new candidate for decreasing pulmonary and renal vascular endothelial permeability and inflammation in clinically relevant causes of lung injury and organ failure.

To investigate the effect of triglyceride administration on the function of the respiratory system in ARDS, Lekka and coworkers measured Pa_O₂/FI_O₂ ratio, compliance of respiratory system, and pulmonary vascular resistance. They observed that the deterioration of lung function and hemodynamics was accompanied by increases in BAL levels of total protein, phospholipids, phospholipase activities, platelet-activating factors, and neutrophils. A high percentage of BAL cells, mainly macrophages, contained lipid droplets in patients with ARDS after lipid administration. The authors concluded that lipids activate neutrophils and macrophages in the intracapillary or alveolar space, leading to their release of inflammatory mediators.

To examine the mechanisms by which ${alpha}$ -melanocyte–stimulating hormone ( ${alpha}$ -MSH) inhibits acute lung injury after renal ischemia, Deng and coworkers studied mice subjected to bilateral renal ischemia. Renal ischemia rapidly activated kidney and lung NF- ${kappa}$ B, p38 mitogen-activated protein kinase, c-Jun, and activator protein-1 pathways, and produced distant lung injury. Intravenous ${alpha}$ -MSH immediately before reperfusion significantly decreased serum creatinine levels, lung edema, and leukocyte accumulation in kidney and lung 4 hours after ischemia/reperfusion. ${alpha}$ -MSH also prevented activation of kidney and lung transcription factors and stress response genes, and lung ICAM-1 and TNF- ${alpha}$ at early time points after renal ischemia/reperfusion. The authors concluded that ${alpha}$ -MSH protects against both kidney and lung damage after renal ischemia, in part, by inhibiting activation of transcription factors and stress genes early after renal injury.

To determine the role of plasma levels of von Willebrand factor in clinical outcome from acute lung injury, Ware and coworkers measured plasma von Willebrand factor levels in 559 patients enrolled in National Institutes of Health ARDS Network studies. Baseline von Willebrand factor levels were similar in patients with and without sepsis, and were significantly higher in nonsurvivors (435 ± 333%) versus survivors (306 ± 209%), even when controlling for severity of illness and the presence of sepsis. Higher von Willebrand factor levels were also associated with fewer organ failure–free days. Ventilator strategy had no effect on von Willebrand factor levels. The authors concluded that the degree of endothelial activation and injury is strongly associated with outcome in acute lung injury/ARDS, regardless of the presence or absence of sepsis, and is not modulated by a protective ventilatory strategy.

To investigate the ability of sphingosine 1-phosphate, a biologically active lipid generated by hydrolysis of membrane lipids, to prevent regional pulmonary edema accumulation, McVerry and coworkers studied mice receiving high VT (17 ml/kg) ventilation-induced lung injury and beagles receiving high VT ventilation with or without intrabronchial LPS (2 mg/kg) instillation. Intravenously delivered sphingosine 1-phosphate significantly reduced shunt formation, BAL protein, and the accumulation of extravascular lung water induced by endotoxin challenge. Axial and vertical density profiles obtained by computed tomographic imaging showed that sphingosine 1-phosphate improved aeration and edema formation in transitional zones between aerated and consolidated lung regions. The authors concluded that sphingosine 1-phosphate represents a novel therapeutic intervention for the prevention of pulmonary edema through decreasing endothelial permeability.

Abe and coworkers generated parabiotic mice by joining green fluorescent protein transgenic mice and wild-type littermates. They investigated if stem/progenitor cells in blood contributed to the regeneration of lung after injury. Wild-type mice received lethal irradiation or intratracheal elastase administration or both. Radiation or the combination of radiation with elastase significantly increased the proportion of bright green cells in the lungs of wild-type mice. By immunostaining, interstitial monocytes/macrophages, subepithelial fibroblast-like interstitial cells and type I alveolar epithelial cells were positive for green fluorescent protein. Approximately 5 to 20% of lung fibroblasts in primary cultures from injured wild-type mice were green fluorescent protein–expressing cells, indicating their origin in blood. The authors concluded that stem/progenitor cells in blood contribute to the repair of radiation-induced lung injury.

Asada and coworkers investigated the expression of peroxisome proliferator–activated receptor ${gamma}$ (PPAR ${gamma}$ ) in alveolar macrophages and assessed its functional role. Studies showed, using reverse transcription–polymerase chain reaction and Western blotting, that there was a strong expression of PPAR mRNA and protein in freshly isolated human alveolar macrophages. Ligands of PPAR ${gamma}$ significantly decreased LPS-induced TNF- ${alpha}$ production by alveolar macrophages. In addition, these ligands markedly upregulated production of CD36, a scavenger receptor that regulates phagocytosis of apoptotic neutrophils. Moreover, ligand-treated alveolar macrophages ingested a significantly higher number of apoptotic neutrophils than untreated macrophages. These data suggest that PPAR ${gamma}$ expressed by alveolar macrophages may have an antiinflammatory role through inhibiting cytokine production and increasing CD36 expression together with enhanced phagocytosis of apoptotic neutrophils. These studies suggest a potential therapeutic role for PPAR ${gamma}$ ligands in inflammatory disorders of the lung.

To determine whether insulin-like growth factor-I contributes to the fibroproliferative phase of ARDS, Krein and coworkers studied lung biopsies from eight patients who displayed organizing diffuse alveolar damage. Immunochemical studies revealed enhanced staining for insulin-like growth factor-I and its receptor, collagen I, collagen III, smooth muscle actin, CD68, and proliferating cell nuclear antigen. Staining for insulin-like growth factor-I and its receptor was prominent in alveolar and interstitial macrophages and in a variety of mesenchymal cells. Staining for insulin-like growth factor-I was correlated with CD68-positive cells, enhanced collagen I, collagen III, and proliferating cell nuclear antigen immunoreactivity, suggesting that the growth factor plays a role in the deposition of protein in the extracellular matrix and the proliferation of cells in the fibroproliferative phase of ARDS. The authors conclude the insulin-like growth factor-I is increased in the fibroproliferative phase of ARDS.

In a state of the art review article, Kinnula and Crapo discuss superoxide dismutase in lung disease.

In a state of the art review article, de Perrot discusses ischemia-reperfusion injury that results after lung transplantation.

Citations 1-11 of 11 total displayed.

Contributions of High Mobility Group Box Protein in Experimental and Clinical Acute Lung Injury

Hiroshi Ueno, Tomoyuki Matsuda, Satoru Hashimoto, Fumimasa Amaya, Yoshihiro Kitamura, Masaki Tanaka, Atsuko Kobayashi, Ikuro Maruyama, Shingo Yamada, Naoki Hasegawa, Junko Soejima, Hidefumi Koh, and Akitoshi Ishizaka
Am. J. Respir. Crit. Care Med. 170: 1310 -1316. First published online as doi:10.1164/rccm.200402-188OC [Abstract] [Full text]

Cells Derived from the Circulation Contribute to the Repair of Lung Injury

Shinji Abe, Craig Boyer, Xiangde Liu, Fu Qiang Wen, Tetsu Kobayashi, Qiuhong Fang, Xingqi Wang, Mitsuyoshi Hashimoto, J. Graham Sharp, and Stephen I. Rennard
Am. J. Respir. Crit. Care Med. 170: 1158 -1163. First published online as doi:10.1164/rccm.200307-908OC [Abstract] [Full text]

Sphingosine 1-Phosphate Reduces Vascular Leak in Murine and Canine Models of Acute Lung Injury

Bryan J. McVerry, Xinqi Peng, Paul M. Hassoun, Saad Sammani, Brett A. Simon, and Joe G. N. Garcia
Am. J. Respir. Crit. Care Med. 170: 987 -993. First published online as doi:10.1164/rccm.200405-684OC [Abstract] [Full text]

Significance of Von Willebrand Factor in Septic and Nonseptic Patients with Acute Lung Injury

Lorraine B. Ware, Mark D. Eisner, B. Taylor Thompson, Polly E. Parsons, and Michael A. Matthay
Am. J. Respir. Crit. Care Med. 170: 766 -772. First published online as doi:10.1164/rccm.200310-1434OC [Abstract] [Full text]

Protective Effects of Sphingosine 1-Phosphate in Murine Endotoxin-induced Inflammatory Lung Injury

Xinqi Peng, Paul M. Hassoun, Saad Sammani, Bryan J. McVerry, Melissa J. Burne, Hamid Rabb, David Pearse, Rubin M. Tuder, and Joe G. N. Garcia
Am. J. Respir. Crit. Care Med. 169: 1245 -1251. First published online as doi:10.1164/rccm.200309-1258OC [Abstract] [Full text]

${alpha}$ -Melanocyte–stimulating Hormone Inhibits Lung Injury after Renal Ischemia/Reperfusion

Jiangping Deng, Xuzhen Hu, Peter S. T. Yuen, and Robert A. Star
Am. J. Respir. Crit. Care Med. 169: 749 -756. First published online as doi:10.1164/rccm.200303-372OC [Abstract] [Full text]

The Impact of Intravenous Fat Emulsion Administration in Acute Lung Injury

Marilena E. Lekka, Stamatis Liokatis, Christos Nathanail, Vasiliki Galani, and George Nakos
Am. J. Respir. Crit. Care Med. 169: 638 -644. First published online as doi:10.1164/rccm.200305-620OC [Abstract] [Full text]

Antiinflammatory Roles of Peroxisome Proliferator–activated Receptor ${gamma}$ in Human Alveolar Macrophages

Kazuhiro Asada, Shigekazu Sasaki, Takafumi Suda, Kingo Chida, and Hirotoshi Nakamura
Am. J. Respir. Crit. Care Med. 169: 195 -200. First published online as doi:10.1164/rccm.200207-740OC [Abstract] [Full text]

Superoxide Dismutases in the Lung and Human Lung Diseases

Vuokko L. Kinnula and James D. Crapo
Am. J. Respir. Crit. Care Med. 167: 1600-1619. [Abstract] [Full text]

Ischemia–Reperfusion–induced Lung Injury

Marc de Perrot, Mingyao Liu, Thomas K. Waddell, and Shaf Keshavjee
Am. J. Respir. Crit. Care Med. 167: 490-511. [Abstract] [Full text]

Localization of Insulin-like Growth Factor-I in Lung Tissues of Patients with Fibroproliferative Acute Respiratory Distress Syndrome

Peter M. Krein, Peter J. B. Sabatini, William Tinmouth, Francis H. Y. Green, and Brent W. Winston
Am. J. Respir. Crit. Care Med. 167: 83-90. [Abstract] [Full text]

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