Contractile Responses and Structure of Small Bronchi Isolated from Rats after 20 Months' Exposure to Ozone

Szarek, John L.; Stewart, Nancy L.; Zhang, Jason Z.; Webb, Jeffrey A.; Valentovic, Monica; Catalano, Paul J.

doi:10.1006/faat.1995.1160

Cited by 8 publications

(5 citation statements)

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“…Consequently, the time at which samples are obtained relative to the exposure protocol is critical. Nonetheless, this new approach to assessing acute lung injury enables the addressing of questions that currently remain unanswered because the method can be combined with specimen preparations applicable to a wide range of biochemical and physiologic analyses (34,(36)(37)(38)(39)(40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

Three-Dimensional Mapping of Ozone-Induced Acute Cytotoxicity in Tracheobronchial Airways of Isolated Perfused Rat Lung

Postlethwait

Joad

Hyde

et al. 2000

Am J Respir Cell Mol Biol

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Acute lung injury induced by reactive oxygen gases such as ozone (O(3)) is focal and site-selective. To define patterns of acute epithelial injury along intrapulmonary airways, we developed a new analytic approach incorporating labeling of permeable cells, airway microdissection, and laser scanning confocal microscopy, and applied it to isolated perfused rat lungs where ventilation and breathing pattern could be controlled. After exposure to O(3) (0, 0.25, 0.5, or 1.0 ppm), lungs were lavaged to assess lactate dehydrogenase (LDH) and protein, or infused with the permeability marker ethidium homodimer-1 (EthD-1) via tracheal cannula, gently lavaged, and fixed by airway infusion. The airway tree of the right middle lobe was exposed by microdissection of the axial pathway down to the terminal bronchioles; the dissection was incubated with a second nuclear dye, YOPRO-1, to label all nuclei; and whole mounts were examined by confocal microscopy. Abundance of EthD-1-positive (injured) cells was estimated as the number per epithelial volume using stereology on Z-series of projected images. For ozone concentrations of 1.0 ppm, lavage fluid LDH and total protein did not increase over controls. Exposure produced a concentration- dependent but nonhomogeneous increase in the abundance of EthD-1-labeled cells in proximal and distal conducting airways both in the main pathway, including terminal bronchioles, and in side branches. Overall, the highest EthD-1 labeling occurred in the side branches of the most proximal part of the airway tree at 1 ppm with the adjacent axial pathway airway having approximately one-third the labeling density. Density of EthD-1-labeled cells was lowest in terminal bronchioles at all O(3) doses. For the model we used, identification of injured epithelial cells by differential permeability and laser confocal microscopy appeared to be highly sensitive and permitted mapping of acute cytotoxicity throughout the airway tree and quantitative comparisons of sites with different branching histories and potential dosimetry rates.

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Section: Discussionmentioning

confidence: 99%

Three-Dimensional Mapping of Ozone-Induced Acute Cytotoxicity in Tracheobronchial Airways of Isolated Perfused Rat Lung

Postlethwait

Joad

Hyde

et al. 2000

Am J Respir Cell Mol Biol

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“…In the ozone example, f is the Michaelis-Menten model (2.1) with Pi := [Rmax,i, log EDso,i] and g is the power of the mean function (pij 18, where B > 0. This popular choice of g offers more flexibility in modeling the heteroscedasticity within rats than the Poisson-like structure assumed by Szarek (1994) and Szarek et al (1995).…”

Section: Hierarchical Modelmentioning

confidence: 99%

“…, m. The linear second-stage model is generally adequate in many applications, possibly by reparameterization of the mean function f , but extension to a nonlinear second stage is straightforward, e.g., by Taylor series. Since the primary objective of Szarek (1994) and Szarek et al (1995) Biometrics, March 2001 is to determine the ozone effect on the Michaelis-Menten parameters, a linear trend may be modeled by A, = [ I 2 aiI2] for rat i exposed to dose ai.…”

Section: Hierarchical Modelmentioning

confidence: 99%

“…To remedy the paucity of long-term data, the Collaborative Ozone Project was initiated to investigate the risks of cancer and lung diseases in rodents following prolonged inhalation. In particular, Szarek (1994) and Szarek et al (1995) evaluated the reactive ability of airway muscles in rats exposed to ozone for 20 months. The rats were randomized to four ozone doses: 0 ppm is the control exposure of filtered air; 0.12 ppm is the quality standard set by the Environmental Protection Agency; 1 ppm is the maximum concentration tolerated by rodents for long-term survival; and 0.5 ppm was chosen at the intermediate level.…”

Section: Motivation and Introductionmentioning

confidence: 99%

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Robust Two‐Stage Estimation in Hierarchical Nonlinear Models

Yeap

Davidian

2001

Biometrics

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Hierarchical models encompass two sources of variation, namely within and among individuals in the population; thus, it is important to identify outliers that may arise at each sampling level. A two-stage approach to analyzing nonlinear repeated measurements naturally allows parametric modeling of the respective variance structure for the intraindividual random errors and interindividual random effects. We propose a robust two-stage procedure based on Huber's (1981, Robust Statistics) theory of M-estimation to accommodate separately aberrant responses within an experimental unit and subjects deviating from the study population when the usual assumptions of normality are violated. A toxicology study of chronic ozone exposure in rats illustrates the impact of outliers on the population inference and hence the advantage of adopting the robust methodology. The robust weights generated by the two-stage M-estimation process also serve as diagnostics for gauging the relative influence of outliers at each level of the hierarchical model. A practical appeal of our proposal is the computational simplicity since the estimation algorithm may be implemented using standard statistical software with a nonlinear least squares routine and iterative capability.

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“…Neben der Atemmechanik wurden aufgrund von Tierexperimenten adaptive Mechanismen auch für die Stimulierbarkeit von Makrophagen (in vitro), die Permeabilität des respiratorischen Epithels und die Stimulierbarkeit des glatten Bronchialmuskels nach Ozonexposition in vivo postuliert [4,25,29]. Die Mechanismen, die zu diesen Anpassungsphänomenen beitragen, sind weitgehend ungeklärt.…”

Section: Erhebliche Individuelle Schwankungen Bei Der Symptomauslösenunclassified

Effekt der nat�rlichen Ozonexposition auf lungenmechanische Me�gr��en bei Grundsch�lern

Bohnet

Kühr

Kopp

et al. 1998

Monatsschrift Kinderheilkunde

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Contractile Responses and Structure of Small Bronchi Isolated from Rats after 20 Months' Exposure to Ozone

Cited by 8 publications

References 0 publications

Three-Dimensional Mapping of Ozone-Induced Acute Cytotoxicity in Tracheobronchial Airways of Isolated Perfused Rat Lung

Three-Dimensional Mapping of Ozone-Induced Acute Cytotoxicity in Tracheobronchial Airways of Isolated Perfused Rat Lung

Robust Two‐Stage Estimation in Hierarchical Nonlinear Models

Effekt der nat�rlichen Ozonexposition auf lungenmechanische Me�gr��en bei Grundsch�lern

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