Glutathione decreases the pulmonary reimplantation response in canine lung autotransplants.

The pulmonary reimplantation response (PRR) is a form of membrane permeability pulmonary edema occurring in lung transplants. The severity of the PRR reflects the quality and duration of lung graft preservation. Free radicals formed during ischemia with reperfusion in the autotransplanted dog lung may play a role in producing PRR. We hypothesized that the addition of reduced glutathione (GSH) to the preservative solution could decrease PRR if hydroperoxides are being formed. Six dogs underwent left lung autotransplantation after the lung was flushed with Euro-Collins solution (EC). These dogs demonstrated radiographic and histopathologic evidence of bilateral pulmonary edema, greatest in the transplanted left lung. They also had increases in lung wet to dry weight (W/D) ratios in both lungs (left, 12.0 +/- 0.9; right, 10.1 +/- 0.8) as compared with a group of five unmanipulated control animals (left, 6.0 +/- 0.5; right, 7.0 +/- 0.4). Malondialdehyde (MDA) concentrations were significantly increased in the transplanted left lungs (14 +/- 4) from this group as compared with the controls (5 +/- 7). Five additional dogs underwent left lung autotransplantation with GSH added to the EC cryopreservation fluid. These animals did not develop histologic or radiographic evidence of pulmonary edema, and W/D ratios as well as MDA concentrations were not different from those in controls. To evaluate the effect of ischemia alone on changes in lung GSH concentrations, ten additional dogs underwent left pneumonectomy. Left lungs were cryopreserved in EC + GSH. In five of the animals, the right lung was removed and preserved in EC alone. In the other five animals, the right lung remained in vivo for 3 h and was then removed. Lung GSH concentrations were doubled after 3 h of ischemia when incubated in EC + GSH compared to in vivo controls and to EC-treated lungs. These data suggest that GSH added to the preservation fluid prevents PRR following transplantation and that lung GSH concentrations actually increase during preservation prior to reimplantation and reperfusion if the lung graft is exposed to GSH in the preservation fluid.

Transbronchial needle aspiration in the diagnosis of bronchogenic carcinoma.

Transbronchial needle aspiration (TBNA) was performed as a diagnostic procedure in 91 consecutive patients ultimately proven to have bronchogenic carcinoma. Results of TBNA were compared, in the same patients, to the diagnostic yield of cytologic examination of sputum, endobronchial brushings and washings, and endobronchial/transbronchial biopsy. The diagnostic yield for sputum was 13 percent (10 of 75); brushings, 40 percent (34 of 84); washings, 29 percent (26 of 89); biopsy, 56 percent (42 of 75); and TBNA, 45 percent (41 of 91). Aspirates were positive in 35 percent of patients with adenocarcinoma, 41 percent with squamous cell carcinoma, 52 percent with large cell undifferentiated carcinoma, and 55 percent of patients with small cell carcinoma. Carinal aspirates were positive in 54 percent (6 of 11); paratracheal aspirates, 57 percent (13 of 23); parabronchial aspirates, 39 percent (11 of 28); endobronchial, 78 percent (7 of 9), and peripheral mass or solitary pulmonary nodule, 40 percent (17 of 42). The overall diagnostic yield for brushings, washings, and biopsy was 64 percent. The addition of TBNA increased the yield to 71 percent. Bronchogenic carcinoma was diagnosed solely by TBNA in six patients, all with extrabronchial or extratracheal lesions. We conclude that TBNA increases the diagnostic yield of bronchoscopy, particularly in patients with extratracheal and extrabronchial lesions. An equally important observation is that TBNA fails to contribute significantly to the diagnosis of cancer in patients with lesions readily accessible by conventional bronchoscopic techniques. Exceptions to this observation include occasional patients with necrotic endobronchial tumors, submucosal lesions, and rarely patients with peripheral lung nodules or masses.

Lung transplantation in a patient with a prior bone marrow transplant.

A 25-year-old woman with acute lymphoblastic leukemia underwent two bone marrow transplants. She subsequently developed severe restrictive lung disease which was successfully treated with a single lung transplant.

Use of the flow-volume loop in the diagnosis of bronchial stenosis after single lung transplantation.

Bronchial complications, including stricture, stenosis, and/or anastomotic dehiscence, are a major cause of morbidity following single lung transplantation. This report describes a 19-year-old man with a diagnosis of end-stage pulmonary fibrosis secondary to prior chemotherapy for non-Hodgkins lymphoma who underwent single lung transplantation. The immunosuppressive regimen included cyclosporine, azathioprine, and methylprednisolone sodium succinate (Solu-Medrol) intravenously for six doses during the first 3 days postoperatively followed by oral prednisone. Sixteen weeks following transplantation, the patient complained of dyspnea. Spirometry revealed a decrease in FEF25-75 and the flow-volume curve demonstrated a bioconcave appearance. The flow-volume loop showed a relatively high initial flow phase occurring over the first 2 to 3 s followed by a low-flow phase. The expiratory phase also showed the same characteristics. Bronchoscopy revealed 75 percent stenosis of the bronchial lumen to the transplanted lung. A transbronchial biopsy specimen obtained at that time was consistent with acute rejection. The patient was treated with a methylprednisolone bolus. A repeated bronchoscopy showed the persistence of stenosis distal to the anastomosis. The patient underwent several bronchoplastic balloon dilatations without complete resolution of the stenosis and a stainless steel mesh stent was placed. Repeated spirometry showed marked improvement of the FEF25-75 and normalization of the flow-volume loop. We conclude that the flow-volume loop curve is a noninvasive procedure that may help monitor the patency of the bronchial anastomoses following single lung transplantation.

Use of balloon-expandable metallic stents in the management of bronchial stenosis and bronchomalacia after lung transplantation.

STUDY OBJECTIVES: Bronchial stenosis (BS) and bronchomalacia (BM) are often associated with lung allograft rejection or infection in lung transplant (LT) recipients. We reviewed our experience using balloon-expandable metallic (Palmaz) stents in the management of BS and BM in LT. DESIGN: Retrospective review of cases. PATIENTS: LT recipients with bronchoscopic and spirometric evidence of BS and BM. INTERVENTIONS: Serial balloon dilation was performed for BS. Stent placement was done for refractory or recurrent BS, or persistent focal BM. RESULTS: Twelve of 129 LT bronchial anastomoses at risk (9.3%) had complications, which included 11 BS and 5 BM. Four BS were accompanied by BM either concurrently or subsequently. The only isolated BM was associated with acute rejection and resolved after appropriate medical therapy. Balloon dilations alone were successful in relieving BS in three cases. Seven patients received a total of 11 stents. Stents were placed under conscious sedation using a flexible bronchoscope. Five of the seven patients had spirometric improvements after stent placements. One patient had no spirometric improvement, and another died before a follow-up study was done. There were no complications during stent placements. However, complications after stent placements included partial dehiscence of the stent from the bronchial wall, stent migration, partial obstruction of a segmental bronchial orifice by a stent in the main bronchus, and longitudinal stent collapse. One stent was successfully removed using a flexible bronchoscope in the endoscopy suite, and two others were removed by rigid bronchoscopy in the operating room. CONCLUSIONS: Endobronchial placement of the Palmaz stent in LT recipients is relatively easy, and it can be removed if needed. However, because there are significant potential complications, the future use of this stent as an airway prosthesis in LT remains unclear.

Single lung transplantation. Alternative indications and technique.

Twenty-two patients have undergone 23 single lung transplants between March 1980 and April 1990 at the University of Texas Health Science Center at San Antonio. The actuarial survival rate is 77.27% at 12 months and 72.73% at 24 months. There have been no instances of bronchial dehiscence or stenosis, even though 13 of the patients were on a program of preoperative prednisone, every patient had high-dose perioperative methylprednisolone, and omental wraps were not used on any bronchial anastomosis. Of particular interest is the fact that three patients had primary pulmonary hypertension, three had secondary pulmonary hypertension, and 10 patients had chronic obstructive pulmonary disease, due in five cases to an alpha 1-antitrypsin deficiency. Each of these entities was previously thought to contraindicate single lung transplantation. Donor selection was based on an oxygen tension/inspired oxygen concentration ratio greater than 300, donor/recipient chest circumference within 3 inches, clear chest x-ray film, negative sputum Gram stain, and less than 6-hour estimated ischemic time. Harvest technique included donor prostaglandin E1 500 micrograms, topical slush, and pulmonoplegia with cold Euro-Collins solution. The heart and lung were separated in situ rather than the heart lung block being removed. A telescoping bronchial anastomosis was performed with 4-0 Prolene (not absorbable) sutures. We conclude that single lung transplantation has evolved into a simple operation, necessitating meticulous preoperative and postoperative care, which can be performed on a wide spectrum of critically ill patients with an acceptable mortality rate.

Cardiopulmonary exercise responses after single lung transplantation for severe obstructive lung disease.

The purpose of this study was to characterize cardiovascular and ventilatory responses to exercise in single lung transplantation (SLT) recipients with nonseptic, severe obstructive lung disease (SLT-OB). We also investigated whether the hyperinflated native lung in SLT-OB recipients could limit normal increases in tidal volume by mechanically constraining the transplanted lung, resulting in ventilation-perfusion imbalance in the lung graft. Data from six SLT-OB recipients (five women, one man) and six age-matched SLT recipients (two women, four men) with severe interstitial lung disease (SLT-IN) were compared. Resting arterial O2 and CO2 tensions were normal and comparable between the SLT groups. Spirometry results were reduced but comparable between SLT groups. Total lung capacity was significantly larger in patients with SLT-OB than in patients with SLT-IN. Diffusion capacity was not different between SLT groups when differences in alveolar volume were accounted for. Quantitative perfusion to the lung graft was comparable between the SLT groups, but quantitative ventilation was greater in patients with SLT-OB than in patients with SLT-IN. Maximum exercise capacity following SLT-OB was decreased, but was comparable to that of SLT-IN recipients. None of the SLT-OB recipients reached predicted maximum minute ventilation and only one experienced mild arterial O2 desaturation, suggesting peripheral muscle abnormalities from corticosteroid use and deconditioning as limiting factors rather than a ventilatory limitation. Tidal volumes at end exercise in the SLT-OB recipients were normal. Our quantitative lung scan and exercise testing data suggest that ventilation-perfusion imbalance and resulting gas exchange abnormalities from lung graft constraint and compression do not occur at rest or with exercise after SLT for obstructive lung disease.

Graft position and pulmonary function after single lung transplantation for obstructive lung disease.

Single lung transplantation (SLT) has become a therapeutic option for the treatment of end-stage obstructive lung disease. Between January 1989 and June 1990, there were 14 patients with end-stage obstructive lung disease who underwent SLT. Eleven of these patients were surviving at 1 year following transplantation. Three of the patients had received left-sided SLT, and eight had received right-sided SLT. In the patients receiving left-sided SLT, the native right lung radiographically appeared to compress the left lung graft. In the patients receiving right-sided SLT, the native left lung did not appear to compress the right lung graft. We hypothesized that right SLT may provide a functional advantage over left SLT for patients with obstructive lung disease. We compared pulmonary function test results before and after transplantation (approximately 3 and 12 months) and compared quantitative ventilation-perfusion lung scan results between the patients with left SLT and those with right SLT. Additionally, we compared graded-exercise test results at 3 and 12 months after transplant between the two groups. Our data revealed no statistical difference in pulmonary function test results or graded-exercise test results between the two groups, although patients undergoing right SLT showed greater increases in FEV1 and forced vital capacity than those undergoing left SLT. Quantitative ventilation and perfusion were greater to the graft in patients receiving right-sided SLT than in patients receiving left-sided SLT, most likely due to the larger size of the right lung. We conclude that there is no functional difference between patients undergoing left or right SLT for end-stage obstructive lung disease.

Ventilation-perfusion inequalities during graft rejection in patients undergoing single lung transplantation for primary pulmonary hypertension.

We report herein data on single lung transplant (SLT) recipients with primary pulmonary hypertension (PPH). One patient did well following surgery but died on the 30th postoperative day due to cytomegalovirus pneumonia. The remaining two patients initially did well with unlimited exercise tolerance following transplantation, but then developed marked dyspnea on exertion and hypoxemia on postoperative days 144 and 120, respectively. Pulmonary function testing showed marked deterioration of function and transbronchial lung biopsy specimens revealed acute graft rejection in one patient and evidence of chronic graft rejection in the second patient. Quantitative ventilation-perfusion lung scanning demonstrated a marked decrease in ventilation to the transplanted lung in both cases associated with only a mild decrease in perfusion. This V/Q mismatch resulted in markedly decreased arterial oxygen saturations, widened alveolar-arterial oxygen gradients, and clinically debilitating dyspnea. We conclude that rejection may result in significant V/Q mismatch and hypoxemia in PPH patients undergoing SLT, which may limit the use of this specific type of surgery for PPH.

Single lung transplantation in patients with systemic disease.

OBJECTIVE: To report functional results and survival in patients undergoing single lung transplantation (SLT) for pulmonary involvement associated with systemic disease or prior malignancy, criteria traditionally considered contraindications to SLT. DESIGN: Case series. SETTING: The University of Texas Health Science Center at San Antonio. PATIENTS: Nine patients who have undergone SLT for end-stage lung disease: four patients with sarcoidosis; two patients with limited scleroderma; and three patients with prior malignancies (two with prior lymphoma and bleomycin-induced pulmonary fibrosis and one who received two bone marrow transplants for acute lymphocytic leukemia and subsequently developed chemotherapy-induced pulmonary fibrosis). MEASUREMENTS: Pulmonary function testing, exercise oximetry, quantitative ventilation-perfusion lung scanning. Actuarial survival. RESULTS: All patients had marked improvement in pulmonary function, exercise oximetry, and quantitative ventilation perfusion to the SLT. One patient with scleroderma died 90 days postoperatively from Pseudomonas pneumonia with a sepsis syndrome. One patient with sarcoidosis died 150 days postoperatively from disseminated aspergillosis. At autopsy, there was no evidence of recurrent fibrosis or sarcoidosis in the transplanted lungs in either of these two patients. The seven surviving patients have returned to work or school and are conducting all activities of daily living without pulmonary disability. The 1- and 2-year actuarial survival rates in these nine patients is 68.6 percent as compared with the 1- and 2-year actuarial survival rates of 66.3 percent and 55.8 percent in the remainder of our SLT group as a whole (n = 49). Despite pharmacologic immunosuppression, there is no evidence of recurrent malignancy in the 3 patients with prior malignancies. CONCLUSIONS: We conclude that carefully selected patients with end-stage lung involvement related to systemic disease or chemotherapy-induced fibrosis may benefit from SLT.

A low incidence of posttransplant lymphoproliferative disorder in 109 lung transplant recipients.

STUDY OBJECTIVES: The incidence of posttransplant lymphoproliferative disorder (PTLD) has been reported to range from 6.4 to 20% in lung transplant (LT) recipients. Postulated contributing factors include Epstein-Barr virus (EBV) infection and the use of immunosuppression, particularly muromonab-CD3 (OKT3)(Orthoclone OKT-3; Ortho Biotech; Raritan, NJ). We sought to examine these PTLD risk factors in 109 LT recipients at our institution who survived > 1 month. DESIGN: Retrospective review of EBV serology of all LT recipients at our institution. Our standard transplant protocol includes OKT3 for induction and refractory rejection, as well as lifelong acyclovir for herpes prophylaxis. We do not perform EBV donor-recipient matching. SETTING: A university-based LT center. RESULTS: We found that 5 of 109 patients were serologically negative for EBV prior to lung transplantation, and all of these patients converted following lung transplantation. The mean time to conversion was 151 days (range, 11 to 365 days). One fatal case of PTLD was documented in an EBV seroconverter (one of five patients) 12 weeks status posttransplantation for lymphangioleiomyomatosis. One nonfatal extrathoracic PTLD was documented in a seropositive patient (1 of 104 patients) 33 months posttransplantation. CONCLUSIONS: We conclude the following: (1) PTLD in LT recipients may have a lower incidence (2 of 109 patients; 1.8%) than previously reported, despite an aggressive immunosuppressive regimen; and (2) the incidence of PTLD is higher in patients with primary EBV infection (20% vs 1%).

Single lung transplantation for primary pulmonary hypertension.

Single lung transplantation has become a therapeutic option for end-stage interstitial lung disease and obstructive lung disease. Our group recently extended this treatment to three patients with primary pulmonary hypertension. All patients had marked decreases in pulmonary artery pressures and pulmonary vascular resistance and increases in cardiac output following single lung transplantation. Spirometry, lung volumes, and diffusion capacity were not different in comparison to preoperative studies. Quantitative ventilation-perfusion scans revealed the majority of perfusion distributed to the transplanted lung, with ventilation approximately equally divided between the native and the transplanted lung. Despite ventilation-perfusion imbalance, there was no resting hypoxemia and there was no arterial oxygen desaturation with exercise. One patient expired on the 30th postoperative day due to cytomegalovirus infection of the lungs. In the remaining two patients, maximum exercise capacity following transplantation was near normal in one recipient and reduced in the second recipient. Of note, there was no evidence of ventilatory limitation or impaired oxygenation during exercise in these two recipients. Although an exaggerated exercise ventilatory response was present, this did not limit exercise performance. This report supports the use of single lung transplantation for the treatment of primary pulmonary hypertension.

Pulmonary artery systolic pressures estimated by echocardiogram vs cardiac catheterization in patients awaiting lung transplantation.

BACKGROUND: At many lung transplant centers, right heart catheterization and transthoracic echocardiogram are part of the routine pre-transplant evaluation to measure pulmonary pressures. Because decisions regarding single vs bilateral lung transplant procedures and the need for cardiopulmonary bypass are often made based on pulmonary artery systolic pressures, we sought to examine the relationship between estimated and measured pulmonary artery systolic pressures using echocardiogram and catheterization, respectively. METHODS: We retrospectively reviewed all patients in our program who had measured pulmonary hypertension (n = 57). Patients with both echocardiogram-estimated and catheterization-measured pulmonary artery systolic pressures performed within 2 weeks of each other were included (n = 19). We analyzed results for correlation and linear regression in the entire group and in the patients with primary pulmonary hypertension (n = 8) and pulmonary fibrosis (n = 8). RESULTS: In patients with primary pulmonary hypertension, pulmonary artery systolic pressure was 94 +/- 27 and 95 +/- 15 mm Hg by echocardiogram and catheterization, respectively, with r(2) = 0.11; in patients with pulmonary fibrosis, 57 +/- 23 and 58 +/- 12 mm Hg with r(2) = 0.22; and in the whole group, 76 +/- 29 and 75 +/- 23 mm Hg with r(2) = 0.50. Thirty-two additional patients had mean pulmonary artery systolic pressure = 48 +/- 16 mm Hg by catheterization but either had no evidence of tricuspid regurgitation by echocardiogram (n = 22) or the pulmonary artery systolic pressure could not be measured (n = 10). CONCLUSIONS: In patients with pulmonary hypertension awaiting transplant, pulmonary artery systolic pressures estimated by echocardiogram correspond but do not serve as an accurate predictive model of pulmonary artery systolic pressures measured by catheterization. Technical limitations of the echocardiogram in this patient population often preclude estimating pulmonary artery systolic pressure.

Exercise performance after lung transplantation.

Heart-lung, double lung, and single lung transplantation have been shown to be effective in the treatment of patients with advanced cardiopulmonary disorders. An overlap in indications occurs for the different procedures, and in many situations the factors that are important in selecting the best operation for a given patient have not been clearly elucidated. To determine whether the anticipated exercise capacity should be an important consideration in the selection of the optimal procedure for a given patient, we compared exercise performance in patients who had undergone the different lung transplantation procedures in the preceding year and were otherwise well. Eleven heart-lung, six double lung, and 16 single lung recipients and 28 control subjects underwent maximal symptom-limited incremental exercise tests using a cycle ergometer. At peak exercise, transplant recipients reached maximum oxygen uptakes in the range of 40% to 60% of predicted values; no significant differences existed between the means of the different transplant groups. Ventilatory factors did not appear to limit exercise in any group. The exercise responses in the transplant subjects were characterized by reduced aerobic capacity and diminished oxygen pulse, factors indicating abnormal cardiovascular performance. Our data indicate that moderate levels of exercise can be anticipated early after heart-lung, double lung, and single lung transplantation. In the absence of substantial differences in exercise capacity, other considerations would appear to be more important in guiding the selection of the optimal lung replacement procedure for an individual patient.

Species variation in lung antioxidant enzyme activities.

Exposure of several different animal models to O2-induced lung injury has revealed marked differences in sensitivity of various species to O2 damage. These differences may be due in part to variation of cellular antioxidant defenses. To characterize lung antioxidant enzyme activities in different species, we measured lung activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT), and glutathione S-transferase (GSH S-trans) in rat, hamster, baboon, and human lung. Soluble lung fractions were also fractionated on Sephadex G-150-S columns and GSH-Px activity was measured using both cumene hydroperoxide and H2O2. This was done to evaluate non-Se-dependent GSH-Px activity in these lung samples. Human lung was obtained at surgery from patients undergoing lobectomy or pneumonectomy for localized lung tumors. SOD activity was similar for all four groups. GSH-Px activity was higher in rat lung than baboon or hamster lung. Lung CAT activity was variable with the highest activity present in the baboon which revealed a lung CAT activity 10 times higher than activity present in the rat. Lung GSH S-trans activities were higher in hamster, baboon, and human lung than in rat lung. Non-Se-dependent GSH-Px was present in rat lung but absent in hamster, baboon, and human lung. We conclude that the hamster was the best model of the animals studied for mimicking human lung antioxidant enzyme activities. Rat lung antioxidant enzyme activities were markedly different from any of the other species examined.

Assessment of injury in transplanted and nontransplanted lungs after 6 h of cold storage with glutathione.

Single-lung transplantation after 3 h of hypothermic storage produces bilateral lung injury [pulmonary reimplantation response (PRR)]. We hypothesized that glutathione (GSH) hypothermic storage would protect both lungs from PRR for extended preservation times and that differences in injury and protection would be realized between the graft and the nontransplanted lung. Mongrel dogs underwent left single-lung autotransplantation after preservation for 5-6 h in Euro-Collins (EC) solution, EC plus exogenous GSH (EC+GSH), or Viaspan (VIA) at 4 degrees C. Lung injury was measured in both lungs after 1 h of reperfusion. EC dogs demonstrated significant increases in lung edema, lipid peroxidation, and alveolar neutrophil recruitment in the lung graft and to a less extent in the nontransplanted right lung compared with control dogs (P < 0.05). Edema, lipid peroxidation, and alveolar neutrophils were significantly reduced in both lungs from EC+GSH and VIA dogs compared with lungs from EC dogs (P < 0.05). An increase in large-pore permeability was measured in the lung graft from EC dogs compared with all other lungs. Bronchoalveolar lavage fluid lactate dehydrogenase and total protein concentrations were elevated in both lungs from all three groups of tranplanted dogs compared with those of control dogs (P < 0.05). These data suggest that GSH-containing solutions attenuate the PRR after 6 h of ischemic hypothermic storage but that the protection is incomplete. Mechanisms of injury affecting the lung graft during the PRR appear to differ from those affecting the nontransplanted lung.

Allopurinol inhibition of neutrophilic alveolar response during hyperoxia.

Allopurinol is a potent xanthine oxidase inhibitor that has been administered to animals to protect tissues from oxidant injury. We hypothesized that allopurinol may protect against oxidant injury by inhibiting the inflammatory response. Male Sprague-Dawley rats were injected daily with vehicle or allopurinol and compared with noninjected controls. Animals were exposed to room air or 90% oxygen for 14 days. At the end of the exposure period, all animals were lavaged and bronchoalveolar lavage fluid (BALF) was examined for cell counts, lactate dehydrogenase (LDH), and protein. BALF neutrophils were significantly increased in oxygen-exposed noninjected controls (33 +/- 7 x 10(3)/mm3) and also in the vehicle-inoculated oxygen-exposed animals (43 +/- 6 x 10(3)/mm3). Allopurinol treatment resulted in a decrease in the neutrophilic alveolar response in oxygen-exposed animals (5.3 +/- 4 x 10(3)/mm3, P < 0.001). These data reveal that oxygen exposure produces a neutrophilic alveolar response that is attenuated by allopurinol treatment. BALF protein and LDH were significantly increased in all inoculated and noninoculated oxygen-exposed animals compared with air-exposed animals. Therefore, allopurinol decreases the neutrophilic alveolar response produced by a hyperoxic exposure in the rat but does not decrease lung injury as assessed by alveolar LDH and protein release.

Protection from hyperbaric oxidant stress by administration of buthionine sulfoximine.

To explore the role of glutathione in protecting rats from hyperbaric hyperoxia, we administered buthionine sulfoximine (BSO) to block gamma-glutamyl cysteine synthase activity and decrease tissue glutathione synthesis. We then exposed these animals and their vehicle-treated matched controls to 100% oxygen at 4 ATA or room air at 1 ATA. After BSO treatment, glutathione concentrations in air-exposed controls decreased 62% in lung, 76% in liver, 28% in brain, and 62% in plasma. Paradoxically, BSO-treated rats were protected from hyperbaric hyperoxia. The BSO-treated animals seized significantly later and had a markedly prolonged time of survival compared with the vehicle-treated controls. We conclude that BSO treatment protects rats from hyperbaric hyperoxia, despite its effects of lowering plasma and tissue glutathione concentrations. This protection may be related to a direct effect of the compound in decreasing free radical-mediated tissue injury, increasing tissue antioxidant defenses, or increasing seizure threshold.

Oxygen toxicity.

Ventilating patients with elevated oxygen tensions alters normal respiratory physiology and may damage lung tissue, depending on coexisting host and iatrogenic factors. Pulmonary oxygen toxicity begins at a cellular level when the generation of reduced oxygen intermediates exceeds local defenses. The mainstay of therapy is prevention. Supplemental oxygen should be prescribed at the lowest concentration possible that will still allow adequate tissue oxygenation. Presently, no specific therapeutic interventions are approved for use in humans to treat pulmonary oxygen toxicity. New agents that act as free radical scavengers or reduce free radical formation may prove useful in future clinical trials based on many of the scientific studies summarized in this review.

Effects of age on rat glutathione metabolism.

The authors hypothesized that rat plasma or tissue glutathione metabolism could change with age due to possible decreases in glutathione-related enzyme activities. To test this hypothesis, the authors measured plasma and tissue concentrations of glutathione and glutathione-related enzymes. Animals were 3 months, 12 months, or 24 months old at the time of experiments. Plasma glutathione was found to be significantly increased in both the 12-month-old and 24-month-old groups compared to the 3-month-old rats. Tissue enzyme measurements showed no significant differences between the groups in lung or liver glutathione peroxidase or glutathione S-transferase. gamma-Glutamyl transpeptidase activity was significantly decreased in kidney and lung with aging. Decreases in tissue gamma-glutamyl transpeptidase activity occur with age; this may contribute to increases in plasma glutathione concentrations.