Ichidai Kudoh

The Effect of Pentoxifylline on Acid-induced Alveolar Epithelial Injury

Background Acid instillation into one lung is known to cause an increase in the permeability of the endothelium to protein in both the instilled and the contralateral lungs. Activated neutrophils are believed to be involved in causing this increased permeability. Pentoxifylline, a drug used in clinical practice, has multiple effects on neutrophils, including inhibition of phagocytosis, degranulation, and superoxide generation. This study investigated whether pretreatment with pentoxifylline would protect the alveolar epithelium or lung endothelium from injury. Methods The effect of acid instillation into one lung of anesthetized rabbits using several quantitative parameters was investigated. The quantification of the bidirectional movement of the alveolar (sup 125 Iodine‐albumin) and the circulating protein tracers (sup 131 Iodine‐albumin) was used as a measurement of the permeabilities of the lung epithelium and the lung endothelium in the acid‐instilled lung. Bronchoalveolar lavage and measurement of the entry of the circulating protein tracer were used to assess the permeabilities of these barriers in the noninstilled lung. Results The instillation of HCl (pH 1.25, 1.2 ml/kg) into the right lung resulted in an increase in the protein permeability of the right lungs alveolar epithelium and endothelium as well as an increase in the permeability to protein of the left lungs endothelium. Pentoxifylline pretreatment attenuated the increase in the endothelial permeability of both lungs by 50% and restored the PaO2 /FI sub O2 to normal in the pretreated animals exposed to acid injury. Conclusions Acid aspiration causes a dramatic increase in the alveolar epithelial permeability of the acid‐instilled lung, but the permeability of the alveolar epithelium of the contralateral lung remains normal. In contrast, unilateral acid instillation causes an increase in the permeability of the endothelium of both lungs. The increase in endothelial permeability can be attenuated by pretreatment with pentoxifylline administration, and this leads to restoration of normal gas exchange.

Activation of alveolar macrophages in acid-injured lung in rats: different effects of pentoxifylline on tumor necrosis factor-alpha and nitric oxide production.

ObjectiveTo determine whether acid instillation augments tumor necrosis factor-&agr; and nitric oxide production by alveolar macrophages in rats, and to study the effects of treatment with pentoxifylline before acid instillation on the production of these inflammatory mediators. DesignControlled laboratory investigation on tumor necrosis factor-&agr; and nitric oxide production by alveolar macrophages of rats that had acid-induced lung injury. SettingUniversity research laboratory. SubjectAlveolar macrophages of rats. InterventionsAlveolar macrophages were recovered by bronchoalveolar lavage at 4, 10, 16, 24, and 72 hrs after unilateral hydrochloric acid (pH, 1.0; volume, 0.1 mL) instillation into the lungs of rats. Alveolar macrophages then were cultured with or without lipopolysaccharide. One group of rats was pretreated with pentoxifylline before acid instillation. Measurements and Main Results Alveolar macrophages from both acid-instilled and contralateral lungs, which had recovered 24 hrs after acid instillation, produced significantly greater tumor necrosis factor-&agr; and nitric oxide. Subsequent exposure to lipopolysaccharide, as a surrogate for bacterial infection, further promoted tumor necrosis factor-&agr; and nitric oxide release. Alveolar macrophages from rats pretreated with pentoxifylline before acid instillation produced significantly less tumor necrosis factor-&agr; and did not overproduce tumor necrosis factor-&agr; when exposed to lipopolysaccharide. In contrast, pretreatment with pentoxifylline had no effect on nitric oxide production by alveolar macrophages. ConclusionsAcid instillation stimulates alveolar macrophages to produce tumor necrosis factor-&agr; and nitric oxide. Pentoxifylline preserved innate production of tumor necrosis factor-&agr; to lipopolysaccharide and did not inhibit the production of bactericidal nitric oxide. This may partly explain why pentoxifylline reduces acid aspiration-induced lung injury while maintaining the host’s ability to combat bacterial infection after acid aspiration.

Neutrophil Elastase Inhibitor, ONO-5046, Modulates Acid-induced Lung and Systemic Injury in Rabbits

Background Acid instillation leads to direct lung and to secondary systemic organ injury, probably via activated macrophages and neutrophils. This study investigated the effects of neutrophil elastase on organ injury after unilateral lung acid instillation by administrating a specific neutrophil elastase inhibitor, ONO-5046, before acid instillation. Methods Three groups of anesthetized rabbits (n = 12 in each group) underwent tracheostomies, and instillations were made into their right lower lobe airspaces with either phosphate buffered saline (pH, 7.4; volume, 1.2 ml/kg; n = 12) or HCl (pH, 1.25; volume, 1.2 ml/kg; n = 24). In half of the acid-instilled rabbits, ONO-5046,10 mg/kg, was given intravenously 15 min before the HCl instillation, and then 10 mg [center dot] kg sup -1 [center dot] h sup -1 of the drug was continuously infused throughout the experiment. The other groups of animals received the vehicle intravenously. Anesthesia and mechanical ventilation was continued for 8 h, whereas arterial blood gases were sampled intermittently. Eight hours after saline or acid instillation, the animals were killed, and their lungs, heart, kidneys, liver, and small intestines were harvested. Wet-to-dry weight ratios (W/D) and myeloperoxidase (MPO) assays of these organs were done, and elastase assays on the bronchoalveolar lavage fluids (BALF) obtained from each lung also were performed. Results Pretreatment with ONO-5046 attenuated the physiologic changes seen in the vehicle-treated animals. Significant decreases in W/D of the noninstilled lungs and of the small intestine and normalization of the oxygenation of the experimental animals occurred. The ONO-5046 pretreatment did not affect the neutrophil sequestration in the lungs or in the other organs as determined by neutrophil counts in BALF and by the MPO assays. Conclusions A neutrophil elastase inhibitor, ONO-5046, administered immediately before acid instillation attenuated the physiologic changes seen in the vehicle-treated animals. The drug blocked neutrophil elastase but did not block neutrophil sequestration in the lungs, although the drug improved measurements of lung injury.

Induction of Cyclooxygenase-2 in Alveolar Macrophages after Acid Aspiration Selective Cyclooxygenase-2 Blockade Reduces Interleukin-6 Production

Background Gastric acid aspiration can result in acute lung injury. In this study, the authors determined whether alveolar macrophages express cyclooxygenase‐2 as a source of inflammatory mediators after acid aspiration. Methods Seventy‐five microliters of hydrochloric acid solution, pH 1.15, was instilled into one lung in mice. After exposure, alveolar macrophages were harvested, and competitive polymerase chain reaction and enzyme‐linked immunosorbent assay were performed to measure expression of cyclooxygenase‐1 and ‐2, interleukin‐1beta and ‐6, tumor necrosis factor‐alpha, and inducible nitric oxide synthase (iNOS). The authors used immunocytochemistry to demonstrate expression of cyclooxygenase‐2 in alveolar macrophages. Selective cyclooxygenase‐2 blockade using N‐2(‐cyclohexyloxy‐4‐nitrophenyl) methane‐sulphonamide was done to characterize prostaglandin‐cytokine interaction. Results Acid aspiration induced upregulation of cyclooxygenase‐2 and interleukin‐6. Tumor necrosis factor‐alpha and iNOS were not upregulated. Interleukin‐1beta was upregulated even with saline instillation but could not be detected in the supernatant of the cell culture. Alveolar macrophages harvested from mice instilled with acid showed a trend toward more production of prostaglandin E2 and produced higher concentrations of interleukin‐6 compared with alveolar macrophages from mice instilled with saline. Selective cyclooxygenase‐2 blockade significantly decreased release of interleukin‐6 from alveolar macrophages harvested from mice instilled with acid. Conclusions Acid aspiration induces strong expression of cyclooxygenase‐2 and production of interleukin‐6 in alveolar macrophages. Selective cyclooxygenase‐2 blockade reduced production of interleukin‐6 by acid‐stimulated alveolar macrophages. These studies suggest that the induction of cyclooxygenase‐2 plays an important role in the systemic inflammatory response induced by acid aspiration.

Complement partially mediates acid aspiration-induced remote organ injury in the rat.

Background:Acid aspiration into one lung is known to cause both a local as well as remote organ injury characterized by neutrophil sequestration and subsequent edema. This study investigated the role of the complement cascade in the development of acid aspiration‐induced local lung and remote organ injuries using K‐76 COONa (K76), an anticomplement agent that inhibits the complement pathway at the C5 step, and its usefulness as a treatment drug.

Placental Transfer and Effects of Famotidine on Neonates

The effect of famotidine on neonates was studied in 34 obstetric patients who underwent elective cesarean section.In the famotidine group, 20 mg of famotidine was intramuscularly injected at 60 min before induction of anesthesia, and 0.5 mg of atropine was injected at 30 min before induction. In the control group, only atropine was given. Ratio of famotidine concentration in the umbilical venous blood to that in the maternal venous blood was determined as 0.64 ± 0.13 (mean ± 3D). No significant differences were noted in the Apgar scores, neonatal gastric acidity, and results of liver function tests between the two groups. No side effect, such as the development of gastrointestinal infections, was observed.

Effects of continuous negative extrathoracic pressure ventilation on left ventricular dimensions and hemodynamics in dogs

It has been reported that continuous negative extrathoracic pressure ventilation (CNETPV) depresses cardiac output less than continuous positive pressure ventilation (CPPV) does, and this difference may be related to the different effects of two ventilatory modes on preload. We performed simultaneous measurements of hemodynamics and left ventricular short axis dimensions by transesophageal echocardiography (TEE) to evaluate left ventricular preload and function during CNETPV and CPPV in normal dogs.Hemodynamic measurements and simultaneous TEE recording were performed at 5 successive periods; 1) the first control period of intermittent positive pressure ventilation (IPPVl), 2) CNETPV with negative end-expiratory pressure (NEEP) of −10 cmH20 (CNETI0), 3) CNETPV with NEEP of −15 cmH20 (CNETI5), 4) the second control period of IPPV (IPPV2), and 5) CPPV with PEEP of 15 cmH20 (CPPVI5). Left ventricular end-systolic and end-diastolic dimension (LVESD and LVEDD), ejection fraction (EF) and fractional shortening (FS) were measured from TEE recordings.Both CNETI0 and CNET15 induced no significant changes in hemodynamics and left ventricular dimensions, compared with those during IPPVl. However, CPPV15 reduced cardiac output and stroke volume (SV) and increased heart rate significantly, compared with IPPV2. CPPV15 significantly decreased LVEDD compared with IPPV2. Neither EF nor FS showed any significant change throughout the experiment.These results indicate that CNETPV preserved cardiac output because it maintained the preload and the left ventricular function.