alpha-naphthyl-thiourea and Respiratory-Distress-Syndrome

Granulocyte colony-stimulating factor is widely prescribed to hasten recovery from cancer chemotherapy-induced neutropenia and has been reported to induce pulmonary toxicity. However, circumstances and mechanisms of this toxicity remain poorly known.. To reproduce a routine situation in cancer patients receiving chemotherapy, we investigated the mechanisms underlying granulocyte colony-stimulating factor-induced exacerbation of alpha-naphthylthiourea-related pulmonary edema.. Laboratory research unit.. Male specific-pathogen-free Sprague-Dawley rats.. The effects of granulocyte colony-stimulating factor given alone or after alpha-naphthylthiourea used to induce acute lung injury were investigated.. Lung injury was assessed based on neutrophil sequestration (myeloperoxidase activity in lung tissue) and influx into alveolar spaces (bronchoalveolar lavage fluid cell quantification) and on edema formation (wet/dry lung weight ratio) and alveolar protein concentration into bronchoalveolar lavage fluid. Tumor necrosis factor-alpha and interleukin-1beta were measured in serum, lung homogenates, and isolated alveolar macrophage supernatants. In control rats, granulocyte colony-stimulating factor (25 microg/kg) significantly elevated circulating neutrophil counts without producing alveolar recruitment or pulmonary edema. alpha-Naphthylthiourea significantly increased the wet/dry lung weight ratio (4.68 +/- 0.04 vs. 4.38 +/- 0.07 in controls, p=.04) and induced alveolar protein leakage. Adding granulocyte colony-stimulating factor to alpha-naphthylthiourea exacerbated pulmonary edema, causing neutrophil sequestration in pulmonary vessels, significantly increasing lung myeloperoxidase activity (12.7 +/- 2.0 mOD/min/g vs. 1.1 +/- 0.4 mOD/min/g with alpha-naphthylthiourea alone; p<.0001), and increasing proinflammatory cytokine secretion. alpha-Naphthylthiourea-related pulmonary edema was not exacerbated by granulocyte colony-stimulating factor during cyclophosphamide-induced neutropenia or after lidocaine, which antagonizes neutrophil adhesion to endothelial cells. Tumor necrosis factor-alpha and interleukin-1beta concentrations in alveolar macrophage supernatants and lung homogenates were significantly higher with alpha-naphthylthiourea + granulocyte colony-stimulating factor than with either agent alone, and anti-tumor necrosis factor-alpha antibodies abolished granulocyte colony-stimulating factor-related exacerbation of alpha-naphthylthiourea-induced pulmonary edema. In rats with cyclophosphamide-induced neutropenia, tumor necrosis factor-alpha concentrations in alveolar macrophage supernatants and lung homogenates were significantly decreased compared with rats without neutropenia.. Granulocyte colony-stimulating factor-related pulmonary toxicity may involve migration of neutrophils to vascular spaces, adhesion of neutrophils to previously injured endothelial cells, and potentiation of proinflammatory cytokine expression.

Topics: Animals; Antineoplastic Agents, Alkylating; Cyclophosphamide; Cytokines; Drug Interactions; Granulocyte Colony-Stimulating Factor; Lung; Male; Neutropenia; Neutrophils; Peroxidase; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Rodenticides; Thiourea

The hypothesis that the changes in the respiratory system pressure- volume (PV) curve during pulmonary edema mainly reflect distal airway obstruction was investigated in rats. Normal rats had a well-defined upper inflection point (UIP) at low airway pressure. Airway occlusion by liquid instillation decreased compliance (Crs) and the volume (Vuip) of the UIP, and increased end-inspiratory pressure. The same changes were observed during the progression of edema produced by high volume ventilation (HV). Changes in Vuip and in Crs produced by HV were correlated with edema severity in normal rats or rats with lungs preinjured with alpha-naphthylthiourea. Vuip and Crs changes were proportional, reflecting compression of the PV curve on the volume axis and suggesting reduction of the amount of ventilatable lung at low airway pressure. In keeping with this explanation, the lower Vuip and Crs were before HV, the more severe HV-induced edema was in alpha-naphthylthiourea-injected rats. When edema was profuse, PV curves displayed a marked lower inflection point (LIP), the UIP at low pressure disappeared but another was seen at high volume above the LIP, and the correlation between Vuip changes and edema severity was lost. These observations may have clinical relevance in the context of the "open lung" strategy.. ventilator-induced lung injury; respiratory mechanics; acute respiratory distress syndrome

Topics: Airway Resistance; Animals; Disease Models, Animal; Inspiratory Capacity; Lung Compliance; Lung Volume Measurements; Male; Predictive Value of Tests; Pulmonary Edema; Rats; Rats, Wistar; Regression Analysis; Respiration, Artificial; Respiratory Distress Syndrome; Severity of Illness Index; Thiourea

Tumor necrosis factor (TNF), a compartmentalized cytokine, is a key mediator in the systemic inflammatory response syndrome and may play a role in multiorgan failure. To assess whether compartmentalization of alveolar TNF is preserved following lung injury, isolated perfused lungs from Sprague-Dawley rats were given intratracheally 1 ml/kg of phosphate-buffered saline (PBS), 0.1 mg/kg of lipopolysaccharide (LPS), or 125,000 units of murine recombinant TNF (mrTNF). To induce lung leak, one group of rats was given 50 mg/kg of alpha-naphthylthiourea (ANTU) intraperitoneally. Then, 125,000 units mrTNF was given intratracheally to these lungs. Samples of perfusate were assayed for TNF by the L929 cytotoxicity assay before (0 min) and 180 min after the intratracheal challenge, and bronchoalveolar lavage (BAL) was performed for TNF assay. ANTU increased lung leak but intratracheal TNF and LPS did not. The isolated perfused lung preparation expressed small amounts of perfusate TNF and underwent minimal leak that was not caused by TNF release. Endogenous or exogenous intrapulmonary TNF remained predominantly compartmentalized, but following ANTU, TNF readily appeared in the perfusate. Compartmentalization of alveolar TNF is lost during alveolar-capillary injury, suggesting that the injured lung may contribute to a systemic inflammatory response and subsequent multiorgan failure.

Topics: Animals; Bronchoalveolar Lavage Fluid; In Vitro Techniques; Lipopolysaccharides; Male; Proteins; Pulmonary Alveoli; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Thiourea; Tumor Necrosis Factor-alpha

Endotoxin injected intraperitoneally caused leucopenia and pulmonary oedema in rats. These effects were spontaneously reversed over the 28 h after the single dose of endotoxin. The pharmacokinetics of three substrates, 14C-sucrose, 3H-prostaglandin E2 (PGE2) and 3H-adenosine, were measured in perfused lungs isolated from rats at different times after treatment with endotoxin. The efflux kinetics of radiolabel derived from sucrose and adenosine were little affected, but that from PGE2 was markedly changed. The metabolism of PGE2 was also decreased. The change in PGE2 pharmacokinetics preceded the pulmonary oedema, but both pharmacokinetics and oedema returned to normal at the same time (28 h after endotoxin). It may be feasible to use PGE2 pharmacokinetics as a biochemical index for early warning of acute lung injury caused by sepsis.

Topics: Adenosine; Animals; Dinoprostone; Endotoxins; Half-Life; In Vitro Techniques; Lung; Male; Pulmonary Edema; Rats; Rats, Inbred Strains; Respiratory Distress Syndrome; Sucrose; Thiourea