Dimethylarginine dimethylaminohydrolase II overexpression attenuates LPS-mediated lung leak in acute lung injury.

Acute lung injury (ALI) is a severe hypoxemic respiratory insufficiency associated with lung leak, diffuse alveolar damage, inflammation, and loss of lung function. Decreased dimethylaminohydrolase (DDAH) activity and increases in asymmetric dimethylarginine (ADMA), together with exaggerated oxidative/nitrative stress, contributes to the development of ALI in mice exposed to LPS. Whether restoring DDAH function and suppressing ADMA levels can effectively ameliorate vascular hyperpermeability and lung injury in ALI is unknown, and was the focus of this study. In human lung microvascular endothelial cells, DDAH II overexpression prevented the LPS-dependent increase in ADMA, superoxide, peroxynitrite, and protein nitration. DDAH II also attenuated the endothelial barrier disruption associated with LPS exposure. Similarly, in vivo, we demonstrated that the targeted overexpression of DDAH II in the pulmonary vasculature significantly inhibited the accumulation of ADMA and the subsequent increase in oxidative/nitrative stress in the lungs of mice exposed to LPS. In addition, augmenting pulmonary DDAH II activity before LPS exposure reduced lung vascular leak and lung injury and restored lung function when DDAH activity was increased after injury. Together, these data suggest that enhancing DDAH II activity may prove a useful adjuvant therapy to treat patients with ALI.

Sodium tanshinone iia sulfonate attenuates seawater aspiration-induced acute pulmonary edema by up-regulating Na(+),K(+)-ATPase activity.

Relieving pulmonary edema is the key of a successful treatment to seawater drowning. Sodium tanshinone IIA sulfonate (STS) has been observed to reduce lung edema from lipopolysaccharide (LPS)-induced lung injury. In this study the authors investigated whether STS attenuates seawater aspiration-induced acute pulmonary edema, and examined the effects of sodium-potassium adensosine triphosphatase (Na(+),K(+)-ATPase) on it. Seawater was instilled through an endotracheal tube. The anesthetized and spontaneously breathing rats received STS intraperitoneally after seawater aspiration. Pao(2), lung wet-to-dry weight ratio, and pulmonary microvascular permeability were tested. The authors explored the effects of STS on the expression and activity of Na(+),K(+)-ATPase in vivo and in vitro. Additionally, the authors investigated the role of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway in the stimulation of Na(+),K(+)-ATPase by STS. The results showed that STS significantly improved hypoxemia, attenuated lung edema, and alleviated seawater-induced lung injury in vivo. Both in vivo and in vitro, it was observed that STS up-regulated the expression and activity of Na(+),K(+)-ATPase. ERK1/2 inhibitor partially blocked the effects of STS on Na(+),K(+)-ATPase activity in alveolar type II cells following seawater incubation. These results indicated that STS could improve seawater aspiration-induced acute pulmonary edema by up-regulating Na(+),K(+)-ATPase activity, and the ERK1/2 signaling pathway may be involved in it.

High hopes at high altitudes: pharmacotherapy for acute mountain sickness and high-altitude cerebral and pulmonary oedema.

The pharmacotherapy of prevention and treatment of acute altitude- related problems - acute mountain sickness, high-altitude cerebral oedema and high-altitude pulmonary oedema - is reviewed. Drug therapy is only part of the answer to the medical problems of high altitude; prevention should include slow ascent and treatment of the more severe illnesses should include appropriate descent. Carbonic anhydrase inhibitors, in particular acetazolamide, remain the most effective drugs in preventing, to a large extent, the symptoms of acute mountain sickness, and can be used in the immediate management of the more severe forms of altitude-related illnesses. Glucocorticoids in relatively large doses are also effective preventative drugs, but at present are largely reserved for the treatment of the more severe acute mountain sickness and acute cerebral oedema. Calcium channel blockers and PDE-5 inhibitors are effective in the management of acute pulmonary oedema. Further work is required to establish the role of antioxidants and anticytokines in these syndromes.

Dexamethasone protects against high-dose endotoxin without loss of tolerance to oxygen.

Endotoxin (500 micrograms/kg)-treated rats are very tolerant to hyperoxia (greater than 95% O2, 1 ATA). We have now attempted to determine if dexamethasone given to rats 1 h before a usually lethal dose of endotoxin would diminish endotoxin's lethality without substantially abrogating its capacity to confer tolerance to hyperoxia. Endotoxin (20 mg/kg) given alone killed 70-80% of air- or O2-breathing rats within 24 h; dexamethasone (0.6 mg) given 1 h before endotoxin decreased mortality at 24 h to 10-15%. About 90% of the rats that were alive 24 h after receiving dexamethasone plus endotoxin (20 mg/kg) survived 72 h of hyperoxia. Dexamethasone plus endotoxin (10 mg/kg) provided as much protection against pulmonary edema resulting from 72 h of hyperoxia as did 500 micrograms/kg endotoxin alone. Tolerance to hyperoxia produced by dexamethasone plus high-dose endotoxin was accompanied by a rise in the activity in the lung of antioxidant enzymes. We conclude that dexamethasone protects rats against the lethal effects of high doses of endotoxin without interfering with endotoxin's capacity to engender tolerance to hyperoxia.

[Various pulmonary lesions induced by high-pressure oxygen]. / Osservazioni relative ad alcune lesioni polmonari indotte dall'ossigeno a forti pressioni

Hyperbaric oxygen may provoke lesions in various organs and tissues depending on the dose and application time. The toxic action mechanisms of oxygen are manifold. The pulmonary lesions that occur in mice submitted to various oxygen pressures are investigated. Anatomo-pathological examination revealed numerous alterations of various kinds depending on pressure used. Emphysema, pulmonary oedema and enormous inflammatory processes in the lung are the most frequent findings encountered in research.

[Reduction of oily substances in rabbit lungs (author's transl)]. / Abbau öliger Substanzen in der Kaninchenlunge

Artificial fat embolism in rabbits was caused by injection of olive oil and Lipiodol Ultrafluid into the ear vein. Electron-microscopic and histochemical observations of the lung were made. The content of nonspecific esterase was evaluated. Serious defects of blood vessels and pneumocytes as well as an increase in alveolar macrophages and capillary thrombosis were noted. The endothelial cells became considerably larger and necrosis of endothelial cells and capillary destruction even occurred. Fat appeared interstially and in the alveolus. Tissue reaction is much greater in olive oil than in contrast medium. This is due to their different chemical composition. The strong tissue reaction in olive oil is caused by glycerol and unsaturated fatty acids occurring in hydrolysis. Fat emboli are primarily eliminated by enzymatic splitting. Normally alveolar macrophages and endothelial cells contain little nonspecific esterase. After application of fatty fluids they react with an increase in the content of esterase. Alveolar epithelium seems to participate in enzymatic fat splitting.