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Maurizio Luisetti - One of the best experts on this subject based on the ideXlab platform.
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whole Lung Lavage therapy for pulmonary alveolar proteinosis a global survey of current practices and procedures
Orphanet Journal of Rare Diseases, 2016Co-Authors: Ilaria Campo, Francesco Bonella, Maurizio Luisetti, Koh Nakata, Matthias Griese, Bruce C Trapnell, Jan C Grutters, Coline H M Van Moorsel, Ulrich Costabel, Vincent CottinAbstract:Background Whole Lung Lavage (WLL) is the current standard of care treatment for patients affected by pulmonary alveolar proteinosis (PAP). However, WLL is not standardized and international consensus documents are lacking. Our aim was to obtain a factual portrayal of WLL as currently practiced with respect to the procedure, indications for its use, evaluation of therapeutic benefit and complication rate.
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whole Lung Lavage therapy for pulmonary alveolar proteinosis a global survey of current practices and procedures
Orphanet Journal of Rare Diseases, 2016Co-Authors: Ilaria Campo, Francesco Bonella, Maurizio Luisetti, Koh Nakata, Matthias Griese, Bruce C Trapnell, Jan C Grutters, Coline H M Van Moorsel, Ulrich Costabel, Vincent CottinAbstract:Whole Lung Lavage (WLL) is the current standard of care treatment for patients affected by pulmonary alveolar proteinosis (PAP). However, WLL is not standardized and international consensus documents are lacking. Our aim was to obtain a factual portrayal of WLL as currently practiced with respect to the procedure, indications for its use, evaluation of therapeutic benefit and complication rate. A clinical practice survey was conducted globally by means of a questionnaire and included 27 centers performing WLL in pediatric and/or adult PAP patients. We collected completed questionnaires from 20 centres in 14 countries, practicing WLL in adults and 10 centers in 6 countries, practicing WLL in pediatric patients. WLL is almost universally performed under general anesthesia, with a double-lumen endobronchial tube in two consecutive sessions, with an interval of 1–2 weeks between sessions in approximately 50 % of centres. The use of saline warmed to 37 °C, drainage of Lung Lavage fluid by gravity and indications for WLL therapy in PAP were homogenous across centres. There was great variation in the choice of the first Lung to be Lavaged: 50 % of centres based the choice on imaging, whereas 50 % always started with the left Lung. The choice of position was also widely discordant; the supine position was chosen by 50 % of centres. Other aspects varied significantly among centres including contraindications, methods and timing of follow up, use of chest percussion, timing of extubation following WLL and Lung isolation and Lavage methods for small children. The amount of fluid used to perform the WLL is a critical aspect. Whilst a general consensus exists on the single aliquot of fluid for Lavage (around 800 ml of warm saline, in adults) great variability exists in the total volume instilled per Lung, ranging from 5 to 40 liters, with an average of 15.4 liters/Lung. This international survey found that WLL is safe and effective as therapy for PAP. However these results also indicate that standardization of the procedure is required; the present survey represents the a first step toward building such a document.
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hereditary pulmonary alveolar proteinosis pathogenesis presentation diagnosis and therapy
American Journal of Respiratory and Critical Care Medicine, 2010Co-Authors: Takuji Suzuki, Maurizio Luisetti, Takuro Sakagami, Lisa R Young, Brenna Carey, Robert E Wood, Susan E Wert, Bruce K Rubin, Katharine Kevill, Claudia ChalkAbstract:Rationale: We identified a 6-year-old girl with pulmonary alveolar proteinosis (PAP), impaired granulocyte-macrophage colony–stimulating factor (GM-CSF) receptor function, and increased GM-CSF. Objectives: Increased serum GM-CSF may be useful to identify individuals with PAP caused by GM-CSF receptor dysfunction. Methods: We screened 187 patients referred to us for measurement of GM-CSF autoantibodies to diagnose autoimmune PAP. Five were children with PAP and increased serum GM-CSF but without GM-CSF autoantibodies or any disease causing secondary PAP; all were studied with family members, subsequently identified patients, and controls. Measurement and Main Results: Eight children (seven female, one male) were identified with PAP caused by recessive CSF2RA mutations. Six presented with progressive dyspnea of insidious onset at 4.8 ± 1.6 years and two were asymptomatic at ages 5 and 8 years. Radiologic and histopathologic manifestations were similar to those of autoimmune PAP. Molecular analysis demonstrated that GM-CSF signaling was absent in six and severely reduced in two patients. The GM-CSF receptor β chain was detected in all patients, whereas the α chain was absent in six and abnormal in two, paralleling the GM-CSF signaling defects. Genetic analysis revealed multiple distinct CSF2RA abnormalities, including missense, duplication, frameshift, and nonsense mutations; exon and gene deletion; and cryptic alternative splicing. All symptomatic patients responded well to whole-Lung Lavage therapy. Conclusions: CSF2RA mutations cause a genetic form of PAP presenting as insidious, progressive dyspnea in children that can be diagnosed by a combination of characteristic radiologic findings and blood tests and treated successfully by whole-Lung Lavage.
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successful whole Lung Lavage in pulmonary alveolar proteinosis secondary to lysinuric protein intolerance a case report
Orphanet Journal of Rare Diseases, 2007Co-Authors: Michele Ceruti, Andrea Adami, Antonia Bolongaro, Aldo Baritussio, Ernesto Pozzi, Giulia M. Stella, G. Rodi, Maurizio LuisettiAbstract:Background Pulmonary alveolar proteinosis (PAP) is a rare disease characterised by accumulation of lipoproteinaceous material within alveoli, occurring in three clinically distinct forms: congenital, acquired and secondary. Among the latter, lysinuric protein intolerance (LPI) is a rare genetic disorder caused by defective transport of cationic amino acids. Whole Lung Lavage (WLL) is currently the gold standard therapy for severe cases of PAP.
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successful whole Lung Lavage in pulmonary alveolar proteinosis secondary to lysinuric protein intolerance a case report
Orphanet Journal of Rare Diseases, 2007Co-Authors: Michele Ceruti, Andrea Adami, Antonia Bolongaro, Aldo Baritussio, Ernesto Pozzi, Giulia M. Stella, G. Rodi, Maurizio LuisettiAbstract:Pulmonary alveolar proteinosis (PAP) is a rare disease characterised by accumulation of lipoproteinaceous material within alveoli, occurring in three clinically distinct forms: congenital, acquired and secondary. Among the latter, lysinuric protein intolerance (LPI) is a rare genetic disorder caused by defective transport of cationic amino acids. Whole Lung Lavage (WLL) is currently the gold standard therapy for severe cases of PAP. We describe the case of an Italian boy affected by LPI who, by the age of 10, developed digital clubbing and, by the age of 16, a mild restrictive functional impairment associated with a high-resolution computed tomography (HRCT) pattern consistent with pulmonary alveolar proteinosis. After careful assessment, he underwent WLL. Two years after WLL, the patient has no clinical, radiological or functional evidence of pulmonary disease recurrence, thus suggesting that WLL may be helpful in the treatment of PAP secondary to LPI.
Peter A. Dargaville - One of the best experts on this subject based on the ideXlab platform.
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fluid recovery during Lung Lavage in meconium aspiration syndrome
Acta Paediatrica, 2013Co-Authors: Peter A. Dargaville, John F. Mills, Beverley Copnell, Ismail Haron, David G Tingay, Jaafar Rohana, Lindsay Mildenhall, Jimmy Kf Lee, Mei-jy JengAbstract:Lung Lavage using two aliquots of 15 mL/kg of dilute surfactant was performed in 30 ventilated infants with severe meconium aspiration syndrome (MAS). Mean recovery of instilled Lavage fluid was 46%, with greater fluid return associated with lower mean airway pressure at 24 h and a shorter duration of respiratory support. Conclusion: Recovery of instilled Lavage fluid is paramount in effective Lung Lavage in MAS and must be afforded priority in the Lavage technique.
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randomized controlled trial of Lung Lavage with dilute surfactant for meconium aspiration syndrome
The Journal of Pediatrics, 2011Co-Authors: Peter A. Dargaville, John F. Mills, Mei-jy Jeng, Beverley Copnell, Ismail Haron, David G Tingay, Jaafar Rohana, Lindsay Mildenhall, Anushree NarayananAbstract:Objective To evaluate whether Lung Lavage with surfactant changes the duration of mechanical respiratory support or other outcomes in meconium aspiration syndrome (MAS). Study design We conducted a randomized controlled trial that enrolled ventilated infants with MAS. Infants randomized to Lavage received two 15-mL/kg aliquots of dilute bovine surfactant instilled into, and recovered from, the Lung. Control subjects received standard care, which in both groups included high frequency ventilation, nitric oxide, and, where available, extracorporeal membrane oxygenation (ECMO). Results Sixty-six infants were randomized, with one ineligible infant excluded from analysis. Median duration of respiratory support was similar in infants who underwent Lavage and control subjects (5.5 versus 6.0 days, P = .77). Requirement for high frequency ventilation and nitric oxide did not differ between the groups. Fewer infants who underwent Lavage died or required ECMO: 10% (3/30) compared with 31% (11/35) in the control group (odds ratio, 0.24; 95% confidence interval, 0.060-0.97). Lavage transiently reduced oxygen saturation without substantial heart rate or blood pressure alterations. Mean airway pressure was more rapidly weaned in the Lavage group after randomization. Conclusion Lung Lavage with dilute surfactant does not alter duration of respiratory support, but may reduce mortality, especially in units not offering ECMO.
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Surfactant therapy for meconium aspiration syndrome: current status.
Drugs, 2005Co-Authors: Peter A. Dargaville, John F. MillsAbstract:Meconium aspiration syndrome (MAS) is an important cause of respiratory distress in the term infant. Therapy for the disease remains problematic, and newer treatments such as high-frequency ventilation and inhaled nitric oxide are being applied with increasing frequency. There is a significant disturbance of the pulmonary surfactant system in MAS, with a wealth of experimental data indicating that inhibition of surfactant function in the alveolar space is an important element of the pathophysiology of the disease. This inhibition may be mediated by meconium, plasma proteins, haemoglobin and oedema fluid, and, at least in vitro, can be overcome by increasing surfactant phospholipid concentration. These observations have served as the rationale for administration of exogenous surfactant preparations in MAS, initially as standard bolus therapy and, more recently, in association with therapeutic Lung Lavage. Bolus surfactant therapy in ventilated infants with MAS has been found to improve oxygenation in most studies, although there are a significant proportion of nonresponders and in many cases the effect is transient. Pooled data from randomised controlled trials of surfactant therapy suggest a benefit in terms of a reduction in the requirement for extracorporeal membrane oxygenation (relative risk 0.48 in surfactant-treated infants) but no diminution of air leak or ventilator days. Current evidence would support the use of bolus surfactant therapy on a case by case basis in nurseries with a relatively high mortality associated with MAS, or the lack of availability of other forms of respiratory support such as high-frequency ventilation or nitric oxide. If used, bolus surfactant should be administered as early as practicable to infants who exhibit significant parenchymal disease, at a phospholipid dose of at least 100 mg/kg, rapidly instilled into the trachea. Natural surfactant or a third-generation synthetic surfactant should be used and the dosage repeated every 6 hours until oxygenation has improved. Lung Lavage with dilute surfactant has recently emerged as an alternative to bolus therapy in MAS, which has the advantage of removing surfactant inhibitors from the alveolar space in addition to augmenting surfactant phospholipid concentration. Combined animal and human data suggest that Lung Lavage can remove significant amounts of meconium and alveolar debris, and thereby improve oxygenation and pulmonary mechanics. Arterial oxygen saturation inevitably falls during Lavage but has been noted to recover relatively rapidly, even in infants with severe disease. Several randomised controlled trials of surfactant Lavage in MAS are underway, and until the results are known, Lavage must be considered an unproven and experimental therapy.
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therapeutic Lung Lavage in the piglet model of meconium aspiration syndrome
American Journal of Respiratory and Critical Care Medicine, 2003Co-Authors: Peter A. Dargaville, John F. Mills, B Headley, Yuen Chan, Lee Coleman, Peter Loughnan, Colin J MorleyAbstract:Therapeutic Lung Lavage is an emerging treatment for meconium aspiration syndrome. Our objective was to investigate the type of fluid and aliquot volume most appropriate for Lung Lavage in this condition. Meconium injury was induced in 2-week-old piglets, followed by a 30 ml/kg Lavage in two aliquots 40 minutes later. Lavage with either dilute bovine surfactant (2.5 mg/ml) or a perfluorocarbon emulsion (20% wt/vol) improved oxygenation compared with a nonLavaged control group, but only with dilute surfactant was there a sustained improvement in oxygenation (alveolar-arterial oxygen difference at 5 hours: dilute surfactant 250 mm Hg; perfluorocarbon emulsion 460 mm Hg; controls 460 mm Hg; p = 0.0031). There was histologic and biochemical evidence of decreased Lung injury in the dilute surfactant group. In a further study, 30 ml/kg dilute surfactant Lavage was performed 40 minutes after meconium injury using either two aliquots of 15 ml/kg, or multiple 3-ml aliquots. Aliquot volume of 15 ml/kg was associated with increased meconium removal, better post-Lavage Lung function, and less Lung injury. Dilute surfactant Lavage using two 15-ml/kg aliquots is an effective therapy in the piglet model of meconium aspiration, and should be evaluated in human infants with this condition.
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Surfactant and surfactant inhibitors in meconium aspiration syndrome.
The Journal of pediatrics, 2001Co-Authors: Peter A. Dargaville, Mike South, Peter N McdougallAbstract:Surfactant indices and inhibitors were measured in Lung Lavage fluid from 8 infants with meconium aspiration syndrome (MAS) who were receiving mechanical ventilation and 11 healthy control subjects. Surfactant phospholipid and surfactant protein A content in MAS was not different from that of control subjects, but concentrations of total protein, albumin, and membrane-derived phospholipid were elevated. All infants with MAS had hemorrhagic pulmonary edema. These findings reinforce the notion of MAS as a toxic pneumonitis with epithelial disruption and proteinaceous exudation.
Hanspeter Witschi - One of the best experts on this subject based on the ideXlab platform.
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concentration response relationships of rat Lungs to exposure to oxidant air pollutants a critical test of haber s law for ozone and nitrogen dioxide
Toxicology and Applied Pharmacology, 1992Co-Authors: Thomas R Gelzleichter, Hanspeter WitschiAbstract:Exposure protocols were designed to ask whether Lung damage in rats exposed to either ozone or nitrogen dioxide is proportional to dose rate or to cumulative dose. Thus, the response of rats to a constant product of concentration of oxidant air pollutant and time of exposure (C {times} T) was evaluated for 3-day exposures over a fourfold range of concentrations of ozone (0.2-0.8 ppm) or of nitrogen dioxide (3.6-14.4 ppm) for exposure durations of 6-24 hr per day. The response of rat Lungs was quantified by changes in total protein content of Lung Lavage supernatants or by changes in content of specific cell types in Lung Lavage pellets. The results of these experiments clearly demonstrate that acute Lung damage is a function of cumulative dose (that is, C {times} T product) for the three highest dose rates tested. However, when exposure duration is extended to include the entire 24-hr period (the lowest dose rate tested), there is a marked attenuation of pulmonary response. Rats were also exposed to mixtures of ozone and nitrogen dioxide with the C {times} T product held constant. The authors results clearly demonstrate that when rats are exposed to combinations of ozone and nitrogen dioxide, Lungmore » damage is a function of peak concentration rather than a function of cumulative dose. This deviation from Haber's Law is attributed to a concentration-dependent, synergistic (greater than additive) response to this specific mixture of oxidant air pollutants.« less
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concentration response relationships of rat Lungs to exposure to oxidant air pollutants a critical test of haber s law for ozone and nitrogen dioxide
Toxicology and Applied Pharmacology, 1992Co-Authors: Thomas R Gelzleichter, Hanspeter WitschiAbstract:Exposure protocols were designed to ask whether Lung damage in rats exposed to either ozone or nitrogen dioxide is proportional to dose rate or to cumulative dose. Thus, the response of rats to a constant product of concentration of oxidant air pollutant and time of exposure (C x T) was evaluated for 3-day exposures over a fourfold range of concentrations of ozone (0.2-0.8 ppm) or of nitrogen dioxide (3.6-14.4 ppm) for exposure durations of 6-24 hr per day. The response of rat Lungs was quantified by changes in total protein content of Lung Lavage supernatants or by changes in content of specific cell types in Lung Lavage pellets. The results of these experiments clearly demonstrate that acute Lung damage is a function of cumulative dose (that is, C x T product) for the three highest dose rates tested. However, when exposure duration is extended to include the entire 24-hr period (the lowest dose rate tested), there is a marked attenuation of pulmonary response. Rats were also exposed to mixtures of ozone and nitrogen dioxide with the C x T product held constant. Our results clearly demonstrate that when rats are exposed to combinations of ozone and nitrogen dioxide, Lung damage is a function of peak concentration rather than a function of cumulative dose. This deviation from Haber's Law is attributed to a concentration-dependent, synergistic (greater than additive) response to this specific mixture of oxidant air pollutants.
Francesco Bonella - One of the best experts on this subject based on the ideXlab platform.
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inhaled rhgm csf molgramostim in the first randomised double blind placebo controlled international trial in patients with autoimmune alveolar proteinosis apap
European Respiratory Journal, 2016Co-Authors: Francesco Bonella, Inge Tarnow, Cecilia Ganslandt, Mette Vinge, Kim Arvid Nielsen, Yoshikazu Inoue, Cliff MorganAbstract:Background: APAP is a rare autoimmune disease with an estimated prevalence of 0.7 per 100,000. APAP is caused by accumulation of surfactant lipids and proteins in the alveoli, leading to progressive respiratory insufficiency. Spontaneous remissions are rare. Current therapy is whole Lung Lavage (WLL) and inhaled recombinant human (rh) granulocyte macrophage-colony stimulating factor (GM-CSF) has been reported as an effective, non-invasive medical therapy in a few uncontrolled studies. Study design: A randomised, double-blind, placebo-controlled multicentre clinical trial in aPAP Patients and inclusion criteria: 42 patients will be included at 16 sites in Europe, Russia, Israel and Japan. Adult patients with diagnosed aPAP (serum anti-GM-CSF antibody positive) and stable or progressive disease according to the necessity to undergo whole Lung Lavage (PaO 2 4% points on 6MWT, and (A-a)DO 2 at screening >25 mmHg) will be randomised to once daily treatment for 24 weeks with: 1) inhaled rhGM-CSF (300 µg); 2) inhaled rhGM-CSF (300 µg) or placebo administered intermittently (7 days on/7 days off); or 3) inhaled placebo. After the double-blind period, patients enter a 48 week open-label follow-up period. WLL will be used as rescue therapy.Primary endpoint: Change from baseline (Δ) in (A-a)DO 2 after 24-weeks treatment. Key secondary endpoints: Number needing WLL, time to WLL, ΔVC (% predicted). Other endpoints: ΔDLCO, ΔFEV/FVC, Δ6MWT; CT and symptom scores. This is the first randomised controlled trial, that will evaluate efficacy and safety of inhaled rhGM-CSF (molgramostim) in aPAP patients.
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whole Lung Lavage therapy for pulmonary alveolar proteinosis a global survey of current practices and procedures
Orphanet Journal of Rare Diseases, 2016Co-Authors: Ilaria Campo, Francesco Bonella, Maurizio Luisetti, Koh Nakata, Matthias Griese, Bruce C Trapnell, Jan C Grutters, Coline H M Van Moorsel, Ulrich Costabel, Vincent CottinAbstract:Background Whole Lung Lavage (WLL) is the current standard of care treatment for patients affected by pulmonary alveolar proteinosis (PAP). However, WLL is not standardized and international consensus documents are lacking. Our aim was to obtain a factual portrayal of WLL as currently practiced with respect to the procedure, indications for its use, evaluation of therapeutic benefit and complication rate.
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whole Lung Lavage therapy for pulmonary alveolar proteinosis a global survey of current practices and procedures
Orphanet Journal of Rare Diseases, 2016Co-Authors: Ilaria Campo, Francesco Bonella, Maurizio Luisetti, Koh Nakata, Matthias Griese, Bruce C Trapnell, Jan C Grutters, Coline H M Van Moorsel, Ulrich Costabel, Vincent CottinAbstract:Whole Lung Lavage (WLL) is the current standard of care treatment for patients affected by pulmonary alveolar proteinosis (PAP). However, WLL is not standardized and international consensus documents are lacking. Our aim was to obtain a factual portrayal of WLL as currently practiced with respect to the procedure, indications for its use, evaluation of therapeutic benefit and complication rate. A clinical practice survey was conducted globally by means of a questionnaire and included 27 centers performing WLL in pediatric and/or adult PAP patients. We collected completed questionnaires from 20 centres in 14 countries, practicing WLL in adults and 10 centers in 6 countries, practicing WLL in pediatric patients. WLL is almost universally performed under general anesthesia, with a double-lumen endobronchial tube in two consecutive sessions, with an interval of 1–2 weeks between sessions in approximately 50 % of centres. The use of saline warmed to 37 °C, drainage of Lung Lavage fluid by gravity and indications for WLL therapy in PAP were homogenous across centres. There was great variation in the choice of the first Lung to be Lavaged: 50 % of centres based the choice on imaging, whereas 50 % always started with the left Lung. The choice of position was also widely discordant; the supine position was chosen by 50 % of centres. Other aspects varied significantly among centres including contraindications, methods and timing of follow up, use of chest percussion, timing of extubation following WLL and Lung isolation and Lavage methods for small children. The amount of fluid used to perform the WLL is a critical aspect. Whilst a general consensus exists on the single aliquot of fluid for Lavage (around 800 ml of warm saline, in adults) great variability exists in the total volume instilled per Lung, ranging from 5 to 40 liters, with an average of 15.4 liters/Lung. This international survey found that WLL is safe and effective as therapy for PAP. However these results also indicate that standardization of the procedure is required; the present survey represents the a first step toward building such a document.
Thomas R Gelzleichter - One of the best experts on this subject based on the ideXlab platform.
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concentration response relationships of rat Lungs to exposure to oxidant air pollutants a critical test of haber s law for ozone and nitrogen dioxide
Toxicology and Applied Pharmacology, 1992Co-Authors: Thomas R Gelzleichter, Hanspeter WitschiAbstract:Exposure protocols were designed to ask whether Lung damage in rats exposed to either ozone or nitrogen dioxide is proportional to dose rate or to cumulative dose. Thus, the response of rats to a constant product of concentration of oxidant air pollutant and time of exposure (C {times} T) was evaluated for 3-day exposures over a fourfold range of concentrations of ozone (0.2-0.8 ppm) or of nitrogen dioxide (3.6-14.4 ppm) for exposure durations of 6-24 hr per day. The response of rat Lungs was quantified by changes in total protein content of Lung Lavage supernatants or by changes in content of specific cell types in Lung Lavage pellets. The results of these experiments clearly demonstrate that acute Lung damage is a function of cumulative dose (that is, C {times} T product) for the three highest dose rates tested. However, when exposure duration is extended to include the entire 24-hr period (the lowest dose rate tested), there is a marked attenuation of pulmonary response. Rats were also exposed to mixtures of ozone and nitrogen dioxide with the C {times} T product held constant. The authors results clearly demonstrate that when rats are exposed to combinations of ozone and nitrogen dioxide, Lungmore » damage is a function of peak concentration rather than a function of cumulative dose. This deviation from Haber's Law is attributed to a concentration-dependent, synergistic (greater than additive) response to this specific mixture of oxidant air pollutants.« less
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concentration response relationships of rat Lungs to exposure to oxidant air pollutants a critical test of haber s law for ozone and nitrogen dioxide
Toxicology and Applied Pharmacology, 1992Co-Authors: Thomas R Gelzleichter, Hanspeter WitschiAbstract:Exposure protocols were designed to ask whether Lung damage in rats exposed to either ozone or nitrogen dioxide is proportional to dose rate or to cumulative dose. Thus, the response of rats to a constant product of concentration of oxidant air pollutant and time of exposure (C x T) was evaluated for 3-day exposures over a fourfold range of concentrations of ozone (0.2-0.8 ppm) or of nitrogen dioxide (3.6-14.4 ppm) for exposure durations of 6-24 hr per day. The response of rat Lungs was quantified by changes in total protein content of Lung Lavage supernatants or by changes in content of specific cell types in Lung Lavage pellets. The results of these experiments clearly demonstrate that acute Lung damage is a function of cumulative dose (that is, C x T product) for the three highest dose rates tested. However, when exposure duration is extended to include the entire 24-hr period (the lowest dose rate tested), there is a marked attenuation of pulmonary response. Rats were also exposed to mixtures of ozone and nitrogen dioxide with the C x T product held constant. Our results clearly demonstrate that when rats are exposed to combinations of ozone and nitrogen dioxide, Lung damage is a function of peak concentration rather than a function of cumulative dose. This deviation from Haber's Law is attributed to a concentration-dependent, synergistic (greater than additive) response to this specific mixture of oxidant air pollutants.
