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Full Text (PDF) B-ENT , 2009, 5, Suppl. 13, 21-37 Defence mechanisms of olfactory neuro-epithelium: mucosa regeneration, metabolising enzymes and transporters J.-B. Watelet *, M. Strolin-Benedetti ** and R. Whomsley *** *Department of Otorhinolaryngology, Ghent University, Belgium; **UCB sa, Colombes, France; ***Shire Pharmaceuticals, Basingstoke, Hampshire, UK Key-words. Olfactory; regeneration; cytochrome; transporters Abstract. Defence mechanisms of olfactory neuro-epithelium: mucosa regeneration, metabolising enzymes and trans - porters. The olfactory neuro-epithelium is highly sensitive to chemicals and its direct microbiological environment. It also plays a role as an interface between the airways and the nervous system, and so it has developed several defence instruments for rapid regeneration or for the detoxification of the immediate environment. This review illustrates three of these defence mechanisms: regeneration of the epithelium, local production of metabolising enzymes and xenobiotic transporters. Toxicants can inflict damage by a direct toxic response. Alternatively, they may require metabolic activation to produce the proximate toxicant. In addition to detoxifying inhaled and systemically derived xenobiotics, the local olfactory metabolism may fulfil multiple functions such as the modification of inhaled odorant, the modulation of endogenous signalling molecules and the protection of other tissues such as the CNS and lungs from inhaled toxicants. Finally, the permeability of nasal and olfactory mucosa is an important efficacy parameter for some anti-allergic drugs delivered by intranasal administration or inhalation. Efflux or update transporters expressed in these tissues may therefore significant - ly influence the pharmacokinetics of drugs administered topically. Introduction matic control or transporter acti - affect this highly differentiated vation, have been the subject of mucosa. Most of what we know Inspired air is brought high into several recent publications. about the toxic action of inhaled the nasal cavity to come in contact This review will provide an compounds is derived from experi - with the olfactory nerves, trig - overview of three major defence mental animal studies. gering the sense of smell, which is mechanisms for toxic or chemical intimately associated with taste. 1 insults to the olfactory mucosa. 1.1. Epidemiology The neuro-epithelium has several The inhalation of a number of instruments for ensuring optimal 1. Chemical injury of the olfac - environmental and industrial olfactory function. The olfactory tory epithelium chemicals can lead to olfactory neuro-epithelium is highly sensi - dysfunction. Even if the list of tive to the chemical or microbio - This section does not look at physi - theoretically toxic chemicals is logical environment and it acts as cal (e.g. irradiation...) or pharma - impressive, they are thought to be an interface between the airways cological injuries to the olfactory responsible for smell disorders in and the nervous system. As a mucosa. Many of the toxicity only 2% of patients. 5 The degree result, it is suspected that it facili - mechanisms are still under inves - of olfactory damage seems to be tates the direct transfection of bac - tigation and the literature is main - related to the timing and duration teria or viruses 2 or the transporta - ly based on case reports, making of the exposure, the concentration tion of chemicals 3,4 into the dura any generalisation hazardous. of the agent, and the intrinsic and nervous system. On the other The limited accessibility to biop - toxicity of the agent. It therefore hand, the defence mechanisms sies of human olfactory epitheli - remains difficult to establish a deployed by the olfactory neuro- um, in conjunction with their complete list of environmental epithelium for rapid regeneration small size, has resulted in an toxicants. Furthermore, the multi - or for detoxification of the imme - almost complete lack of informa - plicity of cofactors makes this diate environment, such as enzy - tion about how toxic compounds analysis even more complex. 22 J.-B. Watelet et al. Table 1 Many dusts produced in industry Major toxicants and industrial agents that may induce smell disorders have also been associated with Classes Agents Reported effect olfactory dysfunction, including grain, silicone, cotton, paper, Major toxic chemicals Benzene or benzol Hyposmia/anosmia cement, lead, coal, chromium, and Butyl acetate Hyposmia/anosmia nickel. Carbon disulphide Hyposmia/anosmia Chronic metal toxicity was Chlorine Hyposmia clearly illustrated in the case of Ethyl acetate Hyposmia/anosmia cadmium during the 1950s. Up Formaldehyde Hyposmia to 60% of people exposed to Hydrogen Hyposmia/anosmia cadmium for more than 10 years 6 Selenide Hyposmia presented an olfactory disorder. Paint solvents : Hyposmia/anosmia The olfactory toxicity of solvents acetone (e.g. acetone, acetophenone, ben - mineral turpentine (turps) zenes...) is mainly due to their true turpentine high lipophilicity. Olfactory naphtha toluene deficit increases with cumulative white spirit exposure. Finally, chronic expo - xylene sure to gases (such as carbon methyl ethyl ketone disulphide, carbon monoxide, Sulphuric acid Hyposmia sulphur dioxide, formaldehyde...) Trichloroethylene Hyposmia/anosmia can also directly affect the Major industrial agents Ashes Hyposmia olfactory mucosa. For example, Cadmium Hyposmia/anosmia exposure to ozone induces an Chalk Hyposmia increase in olfactory thresholds in 7 Chromium Hyposmia healthy controls but there is an adaptation phase after the initial Iron carboxyl Hyposmia experiments. Lead Hyposmia Nickel Hyposmia/anosmia 1.3. Principles underlying Ozone Temporary hyposmia damage to the olfactory mucosa Silicone dioxide Hyposmia Smell disorders secondary to toxic exposure can be due to multiple pathogenesis mechanisms: inflam - mation of the nasal mucosa leading to obstruction, neuro - Table 1 lists the major environ - 1.2.2. Chronic toxicity sensorial lesions, central disorders mental toxicants and their clinical On the other hand, when doses are or a combination of the above. consequences. lower and presented for a long This review will focus mainly period of time, the diagnosis can 1.2. Clinical presentation on peripheral neurosensorial be more difficult to establish and, disorders related to toxic injuries 1.2.1. Acute toxicity because of the long course of to the neuro-epithelium. However, The relationship between toxi - events, many confounding factors it is possible that some toxicants cants and accidental smell disor - also need to be taken into account: could also have a central impact ders is easier to identify when the e.g. age, viral infections, trau - on the smell function, even though exposure is massive and sudden. mas... the supporting data is very frag - The smell disorder can occur Chronic exposure to low levels mentary. within the first seconds or the first of benzene, butyl acetate, for - hours after exposure and can lead maldehyde, and paint solvent has 1.3.1. Histological damage to hyposmia or a transitory or per - been commonly reported with Attempts to link clinical anosmia manent anosmia. associated olfactory dysfunction. to olfactory membrane abnor - Defence mechanisms of olfactory mucosa 23 malities have provided relevant information about the clinical consequences of olfactory tissue damage. 8 After exposure to olfactotoxins, cytotoxicity at the level of the olfactory mucosa is seen almost immediately (in less than 24 h). The tissue damage due to perchloroethylene gas is more persistent in the nasal mucosa of the olfactory region than in the respiratory region. Two weeks after exposure, ciliated epithelial cells, as well as a pseudostratified nonciliated columnar epithelium, begin to appear in the area Figure 1 previously covered by olfactory Chemical structure of 2,6-methylsulphonyl-substituted dichlorobenzene (a) and 3- epithelium and remain for up to methylindole (b), regularly used for anosmia models. 3 months after exposure. A base - ment membrane is also present under the ciliated epithelium, sug - gesting a possible persistence of 1.3.2. Direct or indirect toxicity glands, and an apparent redistribu - basal cells. The olfactory epitheli - tion of CYP immunoreactivity um may therefore be replaced by Toxicants can exert their damaging within sustentacular cells. The ciliated respiratory epithelium. properties in different ways. Some treatment of mice with metyra - The lamina propria of the olfacto - agents, such as methylbromide pone, a CYP inhibitor, at 10 min ry mucosa, however, loses its nor - and 3-methylindole (Figure 1b), prior to and 2, 4, 6, and 8 h after a mal structure, with atrophy of the produce a direct toxic response. 12,13 single dichlobenil injection, pro - olfactory nerves and Bowman’s Other compounds, such as vided some protection against the glands. 9 Interestingly, whereas dimethylamine and 3-methyl - damaging effects of dichlobenil. 18 2,5-methylsulfonyl-substituted sulphate, require metabolic activa - Complementary results suggested dichlorobenzene (diCl-MeSO2-B) tion to produce the proximate that, in mice, 3-aminobenzamide, induces no signs of toxicity in the toxicant . 14-17 another inhibitor of CYP, can olfactory mucosa at doses as high Finally, in addition their direct also reduce the local toxicity as 130 mg/kg (i.p. injection), toxic effects, some toxicants can of dichlobenil in the olfactory necrosis of Bowman’s glands also have a strong impact on the mucosa, probably because of
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