INHALATION ADMINISTRATION OF ALL-TRANS-RETINOIC ACID FOR TREATMENT OF ELASTASE-INDUCED PULMONARY EMPHYSEMA IN FISCHER 344 RATS

A past study demonstrated that all-trans-retinoic acid (ATRA) treatment by intraperitoneal injection in a rat model of elastase-induced emphysema caused tissue regeneration as evidenced by a decrease in alveolar size and lung volume and an increase in alveolar number. We postulated that treatment wi...

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Bibliographic Details
Published in:	Experimental lung research Vol. 30; no. 5; pp. 383 - 404
Main Authors:	March, Thomas H., Cossey, Patricia Y., Esparza, Dolores C., Dix, Kelly J., McDonald, Jacob D., Bowen, Larry E.
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA Informa UK Ltd 01-07-2004 Taylor & Francis
Subjects:	Administration, Inhalation animal models Animals Biological and medical sciences Drug Tolerance elastase emphysema Injections, Intraperitoneal Lung - drug effects Lung - metabolism Lung - pathology Male Medical sciences Pancreatic Elastase - administration & dosage Pharmacology. Drug treatments Pulmonary Emphysema - chemically induced Pulmonary Emphysema - drug therapy Pulmonary Emphysema - pathology Rats Rats, Inbred F344 Respiratory system retinoids Tretinoin - administration & dosage Tretinoin - pharmacokinetics Tretinoin - toxicity Lung disease Animal model animal models Rat Respiratory disease Lung Rodentia Retinoid Inhalation elastase Vertebrata Experimental disease Mammalia Treatment Animal Trans stereoisomer Bronchus disease Obstructive pulmonary disease Emphysema Retinoic acid retinoids Tretinoin
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Summary:	A past study demonstrated that all-trans-retinoic acid (ATRA) treatment by intraperitoneal injection in a rat model of elastase-induced emphysema caused tissue regeneration as evidenced by a decrease in alveolar size and lung volume and an increase in alveolar number. We postulated that treatment with this retinoid by nose-only inhalation exposure would be a more efficient means of targeting damaged lung tissue. Emphysema was induced in male Fischer 344 rats by intratracheal instillation of pancreatic elastase (0.5 IU/g body weight). Four weeks after elastase instillation, animals were treated once daily, 4 days/week, for 3 weeks by exposing them nose-only to aerosolized ATRA (target concentration-time of 3000 or 15,000 mg-min/m3) or by injecting them intraperitoneally with ATRA in cottonseed oil (0.5 or 2.5 mg/kg). Based on estimates of particle deposition in the respiratory tract, inhalation doses were chosen to be consistent with injected doses. Lungs were fixed by inflation with formalin (constant pressure for 6 hours followed by >48 hours of immersion) and were embedded in paraffin. Sections were evaluated by histopathology and stereology. Inhalation exposure to ATRA at both aerosol concentrations caused significant elevations of ATRA in the lung, whereas only the high-dose injection treatment was associated with an elevation of lung ATRA. The mean ATRA concentration from lungs of rats in the high-dose inhalation exposure groups as measured by liquid chromatography-mass spectrometry was approximately 12-fold greater than that of high-dose injection-treated rats. Elastase instillation caused increased lung volumes, irregular alveolar air space enlargement, and fragmentation and attenuation of alveolar septa. Neither inhaled nor injected ATRA reduced the enlarged lung volumes associated with this emphysema model. Stereology demonstrated that alveolar air space enlargement in ATRA-treated rats was similar to that in sham-treated emphysematous animals. Thus, while inhalation treatment caused greater levels of the drug in lung tissue in comparison to that of injection-treated animals, treatment with ATRA by either route of administration did not cause a reversal of lung tissue damage in this model of elastase-induced emphysema.
ISSN:	0190-2148 1521-0499
DOI:	10.1080/01902140490463142