Squamous metaplasia

Subsequent studies have confirmed that the reason for this discrepancy is that the rat is able to rapidly metabolise P-carotene to retinol in the intestine, through the action of intestinal dioxygenase. In contrast humans absorb P-carotene systemically such that plasma levels of P-carotene increase to levels not found in the rodent. A more appropriate animal model is the ferret, which shows a similar metabolism to humans. High levels of plasma P-carotene in the ferret induce the cellular transcription factors c-fos and c-jun, and squamous metaplasia is seen in the lung with or without exposure to cigarette smoke (SCF, 2000). Even after the investment of all these resources it has not been possible for the EU Scientific Committee on Food to set an ADI. 

Liu, C., F. Lian, D. E. Smith, R. M. Russell, and X. D. Wang. 2003. Lycopene supplementation inhibits lung squamous metaplasia and induces apoptosis via up-regulating insulin-like growth factor-binding protein 3 in cigarette smoke-exposed ferrets. Cancer Res 63(12) 3138-3144. 

Two recent studies seem to demonstrate that lycopene is able to counteract the dangerous effects of smoke by acting through a mechanism involving IGF-1 and/or Akt pathways. In the lung of ferrets, it has been shown that cigarette smoke-induced lesions (e.g., squamous metaplasia,... 

Mouse inhalation AM AD 1.4 pm o,2.0 luCeO (MO wks 378 life span radiation fibrosis of lung, squamous metaplasia of bronchi, thickening of arteries, radiation pneumonitis, squamous cell carcinoma 5/14 No No No (1972) Lundgren et ai. 

Herzog and Pletscher (1955) observed squamous metaplasia of the ciliated bronchial epithelium in two patients exposed to undetermined concentrations of phosgene. The metaplasia was observed 3 mo or 3 y postexposure, respectively. 

One of the major toxicity issues in cannabis consumption relates to the fact that it is most often smoked. Cannabis and tobacco smoke, apart from having different psychoactive constituents, are actually very similar in their composition (Hoffman et ai. 1975). Cannabis smoke is mutagenic, which gives it carcinogenic potential (Nahas and Latour 1992). Although no specific reports of lung cancer or emphysema from cannabis smoke exist, it is at least as harmful as tobacco smoke, containing three times as much tar and five times as much carbon monoxide (Wu et al. 1988). Cannabis smoke inflames the airways and reduces respiratory capacity. Airway obstruction and squamous metaplasias may also occur. 

To determine doses to be used in chronic inhalation studies, F344 rats and B6C3Fi mice of both sexes were exposed to 0, 3, 15, or 75 ppm 1,2-dibromoethane for 13 weeks (NTP 1982 Reznik et al. 1980). Lesions occurred in respiratory turbinates in the dorsal portion of the nasal cavity of rats and mice exposed to 75 ppm. Respiratory epithelium was affected with cytomegaly of basal cells, focal hyperplasia, loss of cilia, and squamous metaplasia. Rats exposed to 15 ppm... 

A study was conducted to examine proliferative nasal epithelial lesions in F344 rats following subchronic inhalation of 1,2-dibromoethane at concentrations of 0, 3, 10, or 40 ppm (Nitschke et al. 1981). The study incorporated serial sacrifices and sacrifices after an 88-89-day postexposure period. Rats in the mid - and high-dose groups had hyperplasia of nasal turbinate epithelium rats at the highest dose also exhibited nonkeratinizing squamous metaplasia of respiratory epithelium of the nasal turbinates. 

If the insult persists, hyperplasia (cell proliferation) proceeds and leads to an abnormal epithelium. Injury produced by chronic exposure to irritants such as SO2, NO2, O3, formaldehyde, and tobacco smoke includes undifferentiated basal cells (hyperplasia), squamous metaplasia, and goblet cell metaplasia. In practice, many irritants produce responses between mild and severe, and various combinations of degeneration, inflammation, and proliferation may be observed. 

Inhalation of 7 ppm for 6 hours/day caused necrosis and complete erosion of nasal mucosa after 4 days squamous metaplasia of the respiratory epithelium and focal erosion of the olfactory epithelium with evidence of regeneration of some epithelial surface occurred in mice after 9-14 days at this exposure level." Rats and mice exposed to concentrations as low as 4 ppm for 13 weeks had squamous metaplasia, hyperplasia, and inflammation of the nasal mucosa. ... 

Sneezing, tearing, reddened nose, and lesions of the nasal mucosa were observed in rats exposed at 200ppm for 6.5 hours/day, 5 days/week for 24 weeks. Histopathologic examinations showed squamous metaplasia, suppurative rhinitis, and lymphoid hyperplasia of the respiratory epithelium. 

Rats exposed to 500 ppm 6 hours daily for 5 days exhibited marked eye and nasal irritation, and a number of animals had corneal opacity by the end of the third day the mortality rate was 20%, and at autopsy, findings were acute purulent bronchiolitis and bronchopneumonia. Exposure to 25 ppm for 14 days caused respiratory tract epithelial hyperplasia, squamous metaplasia, and clinical rales. ... 

At lower concentrations, 175-500ppm, less damage to the lower respiratory tract occurred, but inflammation, ulcerative rhinitis, and early squamous metaplasia were observed in the respiratory nasal mucosa. Various species survived 5 ppm of continuous exposure for 90 days without signs of toxicity, but at autopsy, some showed mild inflammatory changes in the lungs." ... 

Rats exposed for 2 years to 400 ppm had increased incidence of papillary adenomas of the nasal cavity the incidences of alveolar/ bronchiolar adenomas or carcinomas (combined) were also increased in the male rats, but not in the females. Nonneoplastic lesions of the nasal cavity included inflammation, epithelial hyperplasia, and squamous metaplasia of the nasal epithelium, as well as atrophy of the olfactory sensory epithelium. Mice exposed at 50 or lOOppm for 2 years had no significant increases in the incidence of neoplastic lesions... 

Oronasal exposure of mice to 2.6ppm led to a 50% decrease in respiratory rate. Mice exposed at 0.3, 1.0, and 2.6ppm 6 hour/day for 4, 9, and 14 days had lesions of the respiratory epithelium including squamous metaplasia, focal necrosis, and keratin exudate that were dose dependent at the lower exposure levels. Lesions persisted 2 weeks after exposure but were decreasing 4 weeks after the end of exposure. No exposure-related lesions were observed in the lungs of exposed mice. 

There was no evidence of carcinogenicity in rats or mice exposed to 0.01, 0.05, or 0.2 ppm for 6 hours/day for 2 years. Pigmentation of the respiratory epithelium occurred in both species, and squamous metaplasia of the laryngeal epithelium occurred in female rats. Geno-toxic assays have been uniformly negative. 

Nasal tumors were induced in rats by inhalation exposure to HMPA for 6-24 months at levels of 50, 100, 400, and 4000 ppb, 6 hours/ day, 5 days week, but not in rats exposed to 10 ppb for 24 months. Most nasal mmors were epidermoid carcinomas and developed from the respiratory epithelium or subepithelial nasal glands, both of which revealed squamous metaplasia or dysplasia in the anterior nasal cavity. 

Other effects were keratinized squamous metaplasia of the trachea (4000ppb) dose-related increases in tracheitis and desquamation of the tracheal epithelium, and bronchitis, desquamation, and regeneration of the bronchial epithelium (100, 400, and 4000 ppb) bone marrow erythropoietic hyperplasia (males, 4000ppb) testicular atrophy (males, 4000 ppb) and degenerative changes in the convoluted tubules of the kidneys. ... 

Dogs also showed squamous metaplasia of the nasal cavity after inhalation exposure to HMPA for 5 months at 400 and 4000 ppb. 

In subcbronic studies HMPA administered by gavage or in tbe drinking water of rats caused lesions in tbe nasal cavity. At 100 ppm in tbe drinking water for 90 days there was epithelial denudation, regeneration, and squamous metaplasia of the nasal cavity. At 1000 ppm nasal toxicity was more severe and testicular atrophy was induced in males. 

Morpholine has also been tested for carcinogenicity by inhalation exposure in rats. Exposure to 10, 50, or 150 ppm 6 hours/day, 5 days/week, for up to 104 weeks was associated with dose-related increases in inflammation of the cornea, inflammation and squamous metaplasia of the turbinate epithelium, and necrosis of the turbinate bones in the nasal cavity, but no significant increase in the incidence of tumors. ... 

Chronic exposure of rats to 1 or 12 ppm 6 hours/day, 5 days/week for 2 years caused an increased incidence of rhinitis, squamous metaplasia, and epidermal carcinomas of the nasal cavity. The lARC has determined that there is sufficient evidence for the carcinogenicity of PGE in animals and that it is possibly carcinogenic to humans. ... 

Male and female mice exposed at concentrations up to 4mg/m 6 hours/day for 104 weeks had clear evidence of carcinogenicity based on increased incidences of alveolar/bron-chiolar neoplasms. In rats similarly exposed at concentrations up to 2 mg/m there was some evidence of carcinogenicity in male rats and equivocal evidence in females based on the occurrence of alveolar/bronchiolar neoplasms. Exposure to vanadium pentoxide also caused a spectrum of nonneoplastic lesions in the respiratory tract including alveolar and bronchiolar epithelial hyperplasia, inflammation, fibrosis, and alveolar histocytosis of the lung. Elyper-plasia of the bronchial lymph node occurred in female mice, and an unusual squamous metaplasia of the lung occurred in rats. ... 

Chronic 2-year studies showed a significant increase in the incidences of adenomas and carcinomas of the nasal cavity in high-dose rats fed diets containing 3000ppm of 2,6-xylidine. The carcinomas were highly invasive and frequently destroyed the nasal turbinates and nasal septum. Rhabdomyosarcomas, a rare tumor of the nasal cavity were also observed in the high-dose male and females. The nonneo-plastic lesions observed in the nasal cavity included acute inflammation, epithelial hyperplasia, and squamous metaplasia. In addition, subcutaneous fibromas and fibrosarcomas occurred in both males and females and there was an increased incidence of neoplastic nodules in the livers of female rats. 

A survey about the dietary habits within the scope of the "National Health and Nutritional Examination Survey" showed that an inverse correlation (Morabia et al., 1989) exists between COPD and vitamin A supply as the only one of 12 examined dietary components. If a diminished supply of vitamin A increases the appearance of obstructive respiratory diseases, a marginal or local vitamin A deficit could be responsible for the observed changes of the respiratory mucosa. Such a deficit results in a loss of cilia, an increase of secreting cells and finally the formation of squamous metaplasia (Biesalski et al., 1985 Chytil, 1985 Shah and Rajalekshmi, 1984). 

Treatment of squamous metaplasia with inhalation of vitamin A... 

At present no biopsy-proven data are available about the impact of inhaled aerosolized analogs of vitamin A on preneoplastic tracheobronchial lesions. The aim of a recent observational was twofold first, to assess the feasibility RP inhalation and second, to investigate the response of epithelial changes (squamous metaplasia and dysplasia) to an inhaled RP aerosol in current smokers and ex-smokers (Kohlhaufl et al., 2001). 

Chopra, D. P., and Joiakim, A. P. (1991). Differences in lectin binding in squamous metaplasia induced by benzo(a)pyrene and vitamin A deficiency in hamster tracheal explants. 

---