Inhalation toxicity studies on cigarette smoke (VII) 6-week comparative experiments using modified flue-cured cigarettes: Histopathology of the conducting airways

Cigarette smoke-induced animal models of chronic obstructive pulmonary disease support the protease-antiprotease hypothesis of emphysema, although which cells and proteases are the crucial actors remains controversial. Inhibition of either serine or metalloproteases produces significant protection against emphysema, but inhibition is invariably accompanied by decreases in the inflammatory response to cigarette smoke, suggesting that these inhibitors do more than just prevent matrix degradation. Direct anti-inflammatory interventions are also effective against the development of emphysema, as are antioxidant strategies; the latter again decrease smoke-induced inflammation. There is increasing evidence for autoimmunity, perhaps directed against matrix components, as a driving force in emphysema. There is intriguing but controversial animal model evidence that failure to repair/failure of lung maintenance also plays a role in the pathogenesis of emphysema. Cigarette smoke produces small airway remodeling in laboratory animals, possibly by direct induction of fibrogenic growth factors in the airway wall, and also produces pulmonary hypertension, at least in part through direct upregulation of vasoactive mediators in the intrapulmonary arteries. Smoke exposure causes goblet cell metaplasia and excess mucus production in the small airways and proximal trachea, but these changes are not good models of either chronic bronchitis or acute exacerbations. Emphysema, small airway remodeling, pulmonary hypertension, and mucus production appear to be at least partially independent processes that may require different therapeutic approaches.

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“…Some studies report significant degrees of goblet cell metaplasia in smoke-exposed rats (84,138,139,177), and this can Fig. 10.…”

Section: Mechanisms Of Goblet Cell Metaplasia Mucus Hypersecretion mentioning

confidence: 96%

Mechanisms of cigarette smoke-induced COPD: insights from animal models

Churg

Cosio²,

Wright³

2008

American Journal of Physiology-Lung Cellular and Molecular Phys

280

193

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“…The 90-day period (and 42-day postinhalation period) is in agreement with Organization for Economic Cooperation and Development Guideline 413 (OECD, 1981), which suggests a 90-day inhalation study on rats to provide information on health hazards that are likely to arise from repeated exposure by the inhala-tion route. Extending the smoke exposure period beyond 90 days in rats does not produce any novel biologically significant histopathological findings (such as neoplasia in the lung) or progression of respiratory tract lesions (Coggins et al, 1989a;Coggins, 1998;Walker et al, 1978b;Wehner et al, 1981).…”

Section: Introductionmentioning

confidence: 99%

Toxicological evaluation of an electrically heated cigarette. Part 4: Subchronic inhalation toxicology

Terpstra¹,

Teredesai

Vanscheeuwijck³

et al. 2003

J of Applied Toxicology

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The biological activity of mainstream smoke from an electrically heated cigarette (EHC) with controlled combustion and from the University of Kentucky Reference Cigarette 1R4F was determined in Sprague Dawley rats exposed nose-only for 90 days, 6 h a day, 7 days per week. For an equivalent response comparison between the two cigarette types, two doses were chosen for the EHC where the anticipated results were in the dynamic range of the 1R4F dose-response curve (four concentrations) for most end points. The number of cigarettes smoked per m(3) of diluted smoke resulted in total particulate matter concentrations of 40 and 90 microg l (-1) for the EHC and 40-170 microg l (-1) for the 1R4F. Biomonitoring indicated achievement of target doses. Mainstream smoke yields were lower for the EHC, with the exception of formaldehyde. No smoke-related mortality, remarkable in-life observations or abnormal gross pathological findings were observed. Smoke- and dose-related clinical pathology and organ weight changes included: increases in segmented neutrophils, some liver parameters and lung and adrenal weight relative to body weight; and decreases in lymphocytes, glucose concentration and spleen weight. Smoke-related histopathological findings in the respiratory tract included epithelial cell hyperplasia, squamous metaplasia, atrophy and accumulation of pigmented alveolar macrophages; they were mostly dose-dependent, more pronounced in the upper than lower respiratory tract and completely or partially reversed by 6 weeks post-inhalation. Qualitatively, the biological effects seen for the EHC and the 1R4F were comparable and similar to those observed in other mainstream smoke inhalation studies. Quantitatively, the biological activity of the EHC mainstream smoke was, on average, 65% lower than that of the 1R4F mainstream smoke on an equal cigarette basis and equivalent activity on an equal TPM basis.

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“…In 1977, Smith 19 investigated the vocal folds of rats and noticed the presence of stratified epithelium and non ciliated columnar pseudostratified epithelium, the latter being more frequently observed and also found on the dorsal aspect of the vocal fold. Walker et al (1978) 20 observed different transitions between various types of epithelium. The non-ciliated columnar pseudostratified epithelium was observed on the area close to the thyroid cartilage, including the vocal fold free border, changing to stratified squamous epithelium on the middle portion which is thinner in this region and thicker in the dorsal region.…”

Section: Discussionmentioning

confidence: 99%

Efeitos da inalação passiva da fumaça de cigarro sobre as pregas vocais de ratos

Duarte¹,

Faria²,

Ceolin³

et al. 2006

Rev. Bras. Otorrinolaringol.

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Few studies have demonstrated the pathologic reactions yielded by smoke inhalation on the airway in rats. Aim: The aim of this study was to analyze the possible histopathological effects produced by chronic cigarette smoke inhalation on the vocal folds of rats. Study design: Experimental. Material and Method: 36 male rats (Rattus norvergicus Wistar strain), aged 60 days, were kept in cages and exposed to inhalation of the smoke produced by 10 cigarettes lit 3 times a day, 7 days a week, for periods of 25, 50 and 75 days, and their respective controls. Thereafter the animals were killed and their larynxes were dissected and submitted to histological processing for achievement of histological sections, which were stained with Hematoxylin and Eosin and analyzed by light microscopy. Results: The rats exposed to smoke displayed smaller (p< 0,05) body mass than the control group. There was hyperplasia and squamous metaplasia in the free edge of the vocal fold and squamous hyperplasia on the middle portion of the vocal fold in all 3 study periods. Moreover, the 50-day group revealed keratinizing metaplasia in this area. Morphological alterations in other areas of the larynx and inflammatory reaction of the lamina propria were also not observed. Conclusion: It was concluded that the passive inhalation of cigarette smoke yields important morphological changes in the vocal fold epithelium, which may progress to neoplasia.

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Inhalation toxicity studies on cigarette smoke (VII) 6-week comparative experiments using modified flue-cured cigarettes: Histopathology of the conducting airways

Cited by 34 publications

References 13 publications

Mechanisms of cigarette smoke-induced COPD: insights from animal models

Mechanisms of cigarette smoke-induced COPD: insights from animal models

Toxicological evaluation of an electrically heated cigarette. Part 4: Subchronic inhalation toxicology

Efeitos da inalação passiva da fumaça de cigarro sobre as pregas vocais de ratos

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