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• W2017381839 abstract "Reactive chemicals have long been associated with toxicity of particular organs. Chemicals may have inherent reactivity, such as acid anhydrides, or become reactive as a consequence of in vivo activation. An example of the latter is the anaesthetic halothane that causes a rare hepatitis in susceptible individuals. When inhaled, the chemical is not reactive but it is metabolized by P450 cytochromes in the liver to yield the reactive trifluoroacetyl (TFA) chloride intermediate [1-3]. The acetylation of protein lysine groups by TFA is believed to result in immunogenic TFA-adducted proteins [4]. Consequently, finding antibodies reactive with TFA-conjugated liver microsomal proteins in sera from patients with this hepatitis suggests association of particular TFA adducted proteins with the hepatitis [5-7]. The report by Griffin et al. [8] describing development of a monoclonal antibody to the potent chemical sensitizer trimellitic anhydride (TMA) is of particular interest. The monoclonal antibody displays hapten specificity in that it detects TMA bound to a variety of proteins. This is important since traditionally only a limited number of proteins (most commonly serum albumin) have been considered as carriers for allergenic haptens. The monoclonal antibody may become an important tool in detecting other TMA-adducted proteins, their cellular and subcellular locations, and in suggesting macromolecular targets involved in disease pathogenesis. The mechanism of sensitization to chemical allergens remains largely unknown. For most, an IgE mechanism has been dismissed since specific IgE antibodies are detected rarely, and atopy is not a predisposing factor [9, 10]. Perhaps knowledge of target (carrier) macromolecules could provide the needed mechanistic insight into the disease process. Knowledge of the macromolecular sites of chemical adduction and the stability of the adducts might aid in elucidation of the sensitization mechanism. Diisocyanates, many of which are recognized to be potent chemical allergens, have shown selective binding to certain proteins [11]. Airborne diisocyanates differ by more than an order of magnitude in their binding affinities with individual serum proteins [11]. Indeed, some diisocyanates, such as hexamethylene diisocyanate (HDI), have been found to be site-specific affinity labels for certain proteins, such as cholinesterase. Yet, other chemicals of the same class show greatly reduced binding to the same protein. Such findings indicate that dramatic differences exist within a chemical class with regard to reactions with individual proteins. To achieve immunological activity, low molecular weight chemicals must function as haptens and bind to a carrier macromolecule. This is demonstrated in the article by Griffin et al. [8] in which conjugates are more powerful inhibitors of immune reactions than are the unbound chemicals. The physicochemical properties that characterize chemical allergens have been described [12, 13]. Those properties most closely associated with allergenicity are transport and reactivity characteristics. Chemicals must reach the appropriate target to manifest their biological activity or toxicity. To gain understanding of the molecular basis of allergenicity of a particular chemical, one must understand its chemistry. Acid anhydrides, such as trimellitic anhydride described by Griffin et al. [8] can react with alcohols to form esters, with amino groups to yield amides, with thiols to yield thiolesters, and with water to form acids [14]. Both in vitro and in vivo studies have provided evidence that acid anhydrides form adducts with lysine [15]. Since acid anhydrides are highly reactive, it is assumed that adduct formation occurs readily upon contact of an appropriate nucleophile with the chemical. Moreover, it is assumed that the immunogenic hapten-conjugate is formed at the site of initial in vivo contact. Recent studies have addressed the site of adduct formation of low molecular weight allergens. The airway epithelium separates the external environment from the internal regions of the lung and body. The asthmatic airway epithelium is characterized by goblet cell hyperplasia and increased mucous adherence. Could this region represent the critical target of inhaled chemical allergens? Exposure of animals [16, 17] and differentiated human bronchial epithelial (HBE) cells [18], to vapours of toluene diisocyanate (TDI), the most frequent cause of occupational asthma, resulted in TDI adduct formation localized predominantly at the apical surface of the airway epithelium. Only a small fraction of adduct was found in the circulation or in other organs, such as liver and spleen [16, 17]. The airway epithelium was the site of TDI binding in mice instilled intrabronchially with TDI [19]. Similarly, hexahydrophthalic acid was localized to the mucosa of the upper airways in guinea pigs and rats exposed to the chemical by inhalation [20]. Evaluation of bronchial biopsy specimens of asthmatic car painters revealed HDI adducts localized to the apical surface of lung epithelial cells [21]. The role of the airway epithelium in the pathogenesis of asthma has received recent attention [22]. The macromolecular targets on differentiated HBE cells appear to differ with individual diisocyanate sensitizers. When generated as a vapour, as occurs industrially, HDI was found to form adducts with a limited number of airway proteins including keratin 18, 11-dihydrodialdehydedehydrogenase and actin [23, 24]. Human endobronchial biopsy samples also indicated HDI adducted to keratin 18 [23, 24]. Exposure of HBE cells to TDI resulted in binding of the diisocyanate vapours to the cilia of the airway cells [18]. Double immunostaining revealed the TDI to be colocalized with ciliary tubulin. Formation of the adduct was concentration and time dependent. Mucus-coated differentiated epithelial cells (Fig. 1) were observed to have lesser amounts of TDI-adducts, suggesting that mucus may protect against the toxic effects of TDI [25]. Exposure of the large airways to reactive chemical allergens. The inhaled chemical hapten (red) reacts with nucleophiles (R-NH2, R-SH) in the airway epithelium to form a hapten conjugate. The hapten may transfer from the original conjugate to a preferred nucleophile. The dendritic cell embodying the hapten-conjugate migrates to lymphoid tissue and presents the conjugate to T lymphocytes thereby initiating the sensitization process. There is growing interest in the concept that the airway epithelium plays a major role in the pathogenesis of asthma. Dendritic cells in the epithelium and submucosa are the primary cells initiating allergen sensitization (see Fig. 1) [26]. The epithelium is a major source of cytokines that stimulate dendritic cell migration to local lymphoid areas, and of proinflammatory mediators that influence development of Th2 cells [22]. Adduction of epithelial cells by chemical allergens appears to affect the sensitization process. HDI adducts on proteins of HBE cells were hypothesized to be neoepitopes involved in stimulating an immune response [23]. Using a lymphoproliferation assay, the adducted polypeptides were found to stimulate proliferation of lymphocytes from HDI asthmatics but not those from HDI-exposed non-asthmatics nor atopics with nonisocyanate induced asthma [23]. The binding of TDI to ciliary tubulin of HBE cells [18] may have considerable impact on the aetiology of TDI asthma. The binding may impair ciliary motion leading to prolonged retention of TDI in the airway and thus effectively increasing exposure to the chemical. Tubulin possesses many sulfhydryl groups and is a subunit of ciliary microtubules. Binding to these cytoskeletal elements may enhance access of external agents to the underlying pulmonary tissue through alterations in cell shape. Through interaction of tubulin with cytoskeletal proteins, adducted tubulin may alter cytoskeleton-mediated signal transduction, potentiating airway inflammation or hyperreactivity. It is not expected that all epithelial cell adducts would have biological significance. Some adducts may have a protective function by scavenging electrophiles and thereby preventing reaction of the electrophilic chemical allergen with a macromolecular target. There is growing evidence that glutathione (GSH), the most abundant cellular nucleophile, may indeed protect against formation of sensitizing chemical adducts [3, 27]. In vitro and in vivo data indicate reaction of electrophilic allergens, such as diisocyanates and acid anhydrides, with soluble nucleophiles such as GSH. In vitro, under conditions of physiological pH and carbonate concentration, a rapid reaction of TDI with GSH yielded predominantly the bis(S-glutathionyl) adduct [28]. In this adduct, each isocyanate group is covalently linked to the sulfhydryl moiety of GSH [28]. Since thiol adduction may be reversible at physiological pH, the ability of the thiol adduct to transfer the isocyanato moiety to a MHC protein was tested in vitro. The isocyanato functionality was readily transferred to nucleophilic MHC protein sites [28] indicating the possibility that thio-reactive haptens may be transferred to proteins not present at the site of initial contact and form a diverse set of haptenated antigens. The question remains, can inhaled highly reactive chemicals gain entrance into cells to react with intracellular thiols? Mice were given TDI intrabronchially and 24 h later lungs were examined for thiol content [29]. Thiol levels were found to be reduced by 30–50%. Most importantly, mass spectrometric analyses identified TDI-GSH adducts in the lung tissue indicating that TDI enters cells and reacts with intracellular GSH [29]. Human lung epithelial cells showed the same response. HBE cells from lung transplant recipients were cultured at an air/liquid interface to achieve differentiation [29] then the monolayers were exposed to TDI vapours at 0, 20, 50 or 100 p.p.b. for 5, 15 or 30 min. Intracellular thiols, measured with a fluorescent dye, were found to be substantially reduced in a time- and dose-dependent manner [25, 29]. The significant thiol modification in HBE cells exposed to low levels of TDI vapour suggests that TDI asthma may be GSH dependent. Thiol depletion would impair pulmonary free radical scavenging and increase susceptibility of the lung not only to TDI, but also to other lung toxicants. Moreover, thiol levels in antigen-presenting cells have been shown to influence Th1-Th2 response patterns [30]. Taken together, these findings imply that the thiol status of particular cells and tissues may be a factor contributing to individual susceptibility to TDI. The marked decrease in intracellular fluorescence occurring within 5 min at 20 p.p.b. TDI [18, 25] indicates the occurrence of TDI-induced oxidative stress and suggests a potential risk factor for development of isocyanate sensitization. By their nature, reactive chemicals will form covalent bonds rapidly with molecules in their immediate environment. The biological consequence of adduct formation depends on the chemical nature of the adduct link, the amount of adduct formed, and the function and location of the adducted molecule(s). When several potential targets exist, but the amount of reactive chemical is limited, the chemical is discriminating in its selection of a target. Adduct formation may have several biological outcomes. Adducts may be protective by acting as molecular scavengers. Adduction to some proteins may have no toxic consequence, but may be appropriate for biological monitoring of exposure. Adduction may cause interference with the function of proteins. Lastly, adduction may result in protein antigenicity. The author is grateful to Dr Ranulfo Lemus for preparation of the figure." @default.
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• W2017381839 title "Bonding and transfer: do epithelial conjugates have a role in chemical asthma?" @default.
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