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Carrie A Redlich - One of the best experts on this subject based on the ideXlab platform.
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Mouse Models of Diisocyanate Asthma
American Journal of Respiratory Cell and Molecular Biology, 2002Co-Authors: Carrie A Redlich, Adam V Wisnewski, Terry GordonAbstract:Occupational asthma is the most commonly reported ocpriate forms and concentrations of Diisocyanates for use in animal models and in vitro studies. cupational lung disease in many industrialized countries. Diisocyanates, highly reactive low molecular weight comClinical Presentation of Diisocyanate Asthma pounds used to make polyurethanes, are the most commonly identified cause of occupational asthma (1). Animal Clinically, the presentation of Diisocyanate asthma can be and clinical studies of Diisocyanate asthma have been more variable and difficult to distinguish from adult onset asthma limited compared with atopic asthma, and our understanddue to other causes. There is a latency period between ing of Diisocyanate pathogenesis is less clear. Unlike typical exposure and onset of symptoms; patients develop respiraallergens that cause asthma, Diisocyanates are extremely tory symptoms after recurrent exposures over months to a reactive compounds, creating great uncertainty regarding few years. Once sensitized, individuals can develop early, the carrier proteins for these chemical haptens in vivo. Redelayed, or dual asthmatic attacks in response to very low search on Diisocyanate asthma has been hampered by this levels of exposure, making control difficult. Disease can uncertainty, as well as the lack of mouse models that replipersist away from exposure, emphasizing the importance cate the human disease. Recent studies have made signifiof early diagnosis (6, 7). It is estimated that 5%–15% of cant progress tackling both of these difficult problems. In exposed workers develop asthma (8, 9). However, exposure the present issue of AJRCMB, Matheson and colleagues and host risk factors are not well understood. Unlike many (2) investigate the role of tumor necrosis factor (TNF)types of asthma, atopy is not a risk factor for Diisocyanatein a mouse model of toluene Diisocyanate (TDI) asthma. induced disease. Certain human leukocyte antigen alleles This Perspective will discuss these findings and address key and glutathione S-transferase haplotypes have been associissues that have hindered progress in understanding diisocyated with Diisocyanate asthma, but this has not been conanate asthma and in developing better diagnostic tools. firmed (10–12). Several other recent promising mouse models that should The diagnosis of Diisocyanate asthma remains quite facilitate future research are also discussed. problematic and a challenge for physicians. Clinical history, The major Diisocyanates currently in use are diphenylquestionnaires, and physiologic studies frequently are not definitive (13, 14). Immunologic tests, although of great methane Diisocyanate, toluene Diisocyanate, and hexamethinterest, have shown variable correlation with disease. The ylene Diisocyanate (HDI) (Figure 1). The characteristics of prevalence of Diisocyanate-specific IgG and IgE antibodies Diisocyanate exposure that determine risk are unclear. Both among individuals with Diisocyanate asthma is variable and the respiratory tract and skin are considered important not closely associated with disease (13–18). Diisocyanateroutes of exposure and sensitization (3, 4). Depending on specific lymphocyte proliferation or cytokine enhancement the specific Diisocyanate, exposures can occur as an aerosol have also been investigated, but correlation with disease and/or as a vapor, as well as different monomeric and polyhas been variable (19–21). A promising study by Bernstein meric species, making airborne monitoring difficult (5). This and colleagues recently reported that monocyte chemoatcomplexity of exposure, along with the marked chemical tractant protein-1 (MCP-1) in vitro production had a sensireactivity, greatly adds to the difficulty of generating approtivity and specificity of 79% and 91% in diagnosing Diisocyanate asthma (16). Specific inhalation challenge is considered the “gold standard” for diagnosis. However, such testing is (Received in original form August 26, 2002) neither 100% sensitive nor specific, nor is it readily available
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a novel mouse model of Diisocyanate induced asthma showing allergic type inflammation in the lung after inhaled antigen challenge
The Journal of Allergy and Clinical Immunology, 2002Co-Authors: Christina A Herrick, Adam V Wisnewski, Carrie A Redlich, Lan Xu, Kim BottomlyAbstract:Abstract Background: Exposure to Diisocyanates, a group of highly reactive, low-molecular-weight compounds, is a major cause of occupational asthma. In contrast to mouse models of atopic asthma, previous mouse models of Diisocyanate-induced asthma have failed to show lung inflammation with characteristics of human disease. Objective : Our goal was to establish a novel mouse model of Diisocyanate-induced asthma in which lung inflammation reminiscent of that seen in human asthma is generated after inhaled antigen challenge. Methods : BALB/c mice were epicutaneously sensitized to hexamethylene Diisocyanate (HDI) and then challenged with an HDI-protein conjugate administered by means of an intranasal droplet. Results : HDI sensitization resulted in development of contact hypersensitivity and HDI-specific antibody production. Most importantly, however, vigorous inflammatory responses with characteristics of human asthma were generated in the lung after inhaled HDI challenge. Challenge of sensitized, but not unsensitized, mice resulted in airway eosinophilia, mucus hypersecretion, and production of T H 1-type (IFN-γ) and T H 2-type (IL-4, IL-5, and IL-13) cytokines by lung inflammatory cells. Despite the mixed T H 1/T H 2 response induced by HDI sensitization, use of cytokine-deficient mice revealed that airway eosinophilia was mediated by T H 2 cytokines and not by IFN-γ. Conclusion : We report a novel mouse model of Diisocyanate-induced asthma that, in contrast to previous models, demonstrates antigen-induced lung inflammation with characteristics of human disease. This model will allow investigation of the immunopathogenesis of Diisocyanate-induced asthma and should provide insight into this common form of occupational disease. (J Allergy Clin Immunol 2002;109:873–8.)
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Diisocyanate asthma clinical aspects and immunopathogenesis
International Immunopharmacology, 2002Co-Authors: Carrie A Redlich, Meryl H. KarolAbstract:Diisocyanates, highly reactive chemicals used in the production of polyurethanes, are currently the most frequently reported cause of chemically induced occupational asthma and their use continues to rise. The prevalence of Diisocyanate asthma among exposed workers is estimated to range from 5% to 15%. Routes of exposure include the respiratory tract and skin. Workplace exposures are difficult to quantify and control, and there is no simple diagnostic test for the disease. This review considers recent concepts in exposure, clinical aspects and pathogenesis of the disease. The pathogenesis of Diisocyanate asthma remains unclear, with evidence supporting both immunological and nonimmunological mechanisms. Knowledge of the chemical reactivity of Diisocyanates, the target biomolecules, and the cellular sites of reaction are fundamental to understanding Diisocyanate toxicity and disease. Recent findings of chemical interactions with biological nucleophiles will be described. The importance of Diisocyanate-adducted biomolecules will be emphasized and their potential contributions to pathogenesis discussed. It is anticipated that greater understanding of the immunopathogenesis of Diisocyanate asthma, including the initial cell/Diisocyanate reactions, should lead to clinically useful markers of exposure and early disease.
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identification of human lung and skin proteins conjugated with hexamethylene Diisocyanate in vitro and in vivo
American Journal of Respiratory and Critical Care Medicine, 2000Co-Authors: Adam V Wisnewski, Ranjana Srivastava, Christina Herick, Ranulfo Lemus, Hilary Cain, Nadine Magoski, Kim Bottomly, Meryl H. Karol, Lan Xu, Carrie A RedlichAbstract:Diiisocyanates are asthma-causing chemicals used in the commercial production of polyurethane. We have previously shown that human lung epithelial cell proteins can become conjugated with hexamethylene Diisocyanate (HDI) and may be biologically important in Diisocyanate-induced asthma. The objective of this study was to identify specific human lung and skin proteins that become conjugated with Diisocyanate after in vitro and in vivo exposure. Following in vitro exposure of human airway epithelial cells (A549), keratin 18, the 78-kD glucose-regulated protein, trans-1,2-dihyrobenzene-1,2-diol dehydrogenase, and actin were identified as prominent Diisocyanate-conjugated proteins through use of a combination of immunocytochemical and mass spectrometric techniques. Following in vivo inhalation of an HDI aerosol, keratin 18 was also identified as the predominant Diisocyanate-conjugated protein in human endobronchial biopsy samples, whereas albumin was the predominant Diisocyanate-conjugated protein in bronchoal...
Mohsen Miraftab - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and characterization of polyurethane-based shape-memory polymers for tailored Tgaround body temperature for medical applications
Macromolecular Chemistry and Physics, 2011Co-Authors: Manzoor Ahmad, Peter James King, Hendra Purnawali, Wei Min Huang, Jikui Luo, Paul R. Chalker, Yong Qing Fu, Bin Xu, Mohsen MiraftabAbstract:Various polyurethane-based SMPUs were synthesized using five types of polyols as soft segments and two different Diisocyanates as hard segments. The effects of Diisocyanate concentration on material properties such as crystallinity, transition temperature, shape-memory effect and tensile strength were investigated. SMPUs with a maximum strain near 1000%, recovery rate up to â98%, fixity up to â90% and Tgs of 35-45°C were obtained. A high MDI content results in SMPUs with better shape-memory effect, whereas increasing IPDI content leads to a weaker shape-memory effect. High IPDI concentration seems to prevent or restrict chemical reactions and crosslinks between the polyols and the hard segments, leading to large phase separation and coexistence of soft and hard segments in the macrophases. The properties of polyurethane-based SMPUs are studied systematically using five types of soft segment polyols and two different Diisocyanate hard segments. By varying the concentration of the Diisocyanates and the ratio of MDI to IPDI, it was found that crystallinity, transition temperature, shape-memory effect, and tensile strength can be tailored. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Kim Bottomly - One of the best experts on this subject based on the ideXlab platform.
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a novel mouse model of Diisocyanate induced asthma showing allergic type inflammation in the lung after inhaled antigen challenge
The Journal of Allergy and Clinical Immunology, 2002Co-Authors: Christina A Herrick, Adam V Wisnewski, Carrie A Redlich, Lan Xu, Kim BottomlyAbstract:Abstract Background: Exposure to Diisocyanates, a group of highly reactive, low-molecular-weight compounds, is a major cause of occupational asthma. In contrast to mouse models of atopic asthma, previous mouse models of Diisocyanate-induced asthma have failed to show lung inflammation with characteristics of human disease. Objective : Our goal was to establish a novel mouse model of Diisocyanate-induced asthma in which lung inflammation reminiscent of that seen in human asthma is generated after inhaled antigen challenge. Methods : BALB/c mice were epicutaneously sensitized to hexamethylene Diisocyanate (HDI) and then challenged with an HDI-protein conjugate administered by means of an intranasal droplet. Results : HDI sensitization resulted in development of contact hypersensitivity and HDI-specific antibody production. Most importantly, however, vigorous inflammatory responses with characteristics of human asthma were generated in the lung after inhaled HDI challenge. Challenge of sensitized, but not unsensitized, mice resulted in airway eosinophilia, mucus hypersecretion, and production of T H 1-type (IFN-γ) and T H 2-type (IL-4, IL-5, and IL-13) cytokines by lung inflammatory cells. Despite the mixed T H 1/T H 2 response induced by HDI sensitization, use of cytokine-deficient mice revealed that airway eosinophilia was mediated by T H 2 cytokines and not by IFN-γ. Conclusion : We report a novel mouse model of Diisocyanate-induced asthma that, in contrast to previous models, demonstrates antigen-induced lung inflammation with characteristics of human disease. This model will allow investigation of the immunopathogenesis of Diisocyanate-induced asthma and should provide insight into this common form of occupational disease. (J Allergy Clin Immunol 2002;109:873–8.)
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identification of human lung and skin proteins conjugated with hexamethylene Diisocyanate in vitro and in vivo
American Journal of Respiratory and Critical Care Medicine, 2000Co-Authors: Adam V Wisnewski, Ranjana Srivastava, Christina Herick, Ranulfo Lemus, Hilary Cain, Nadine Magoski, Kim Bottomly, Meryl H. Karol, Lan Xu, Carrie A RedlichAbstract:Diiisocyanates are asthma-causing chemicals used in the commercial production of polyurethane. We have previously shown that human lung epithelial cell proteins can become conjugated with hexamethylene Diisocyanate (HDI) and may be biologically important in Diisocyanate-induced asthma. The objective of this study was to identify specific human lung and skin proteins that become conjugated with Diisocyanate after in vitro and in vivo exposure. Following in vitro exposure of human airway epithelial cells (A549), keratin 18, the 78-kD glucose-regulated protein, trans-1,2-dihyrobenzene-1,2-diol dehydrogenase, and actin were identified as prominent Diisocyanate-conjugated proteins through use of a combination of immunocytochemical and mass spectrometric techniques. Following in vivo inhalation of an HDI aerosol, keratin 18 was also identified as the predominant Diisocyanate-conjugated protein in human endobronchial biopsy samples, whereas albumin was the predominant Diisocyanate-conjugated protein in bronchoal...
M Tuppurainen - One of the best experts on this subject based on the ideXlab platform.
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Long-term follow-up of hexamethylene Diisocyanate-, diphenylmethane Diisocyanate-, and toluene Diisocyanate-induced asthma.
American journal of respiratory and critical care medicine, 2020Co-Authors: Paivi Piirila, Ritva Luukkonen, Suvipaivikki Salo, Timo Tuomi, H Nordman, H M Keskinen, M TuppurainenAbstract:In 1976-1992 245 new cases of asthma induced by Diisocyanates were diagnosed, caused by hexamethylene Diisocyanate (HDI) in 39%, diphenylmethane Diisocyanate (MDI) in 39%, and toluene Diisocyanate (TDI) in 17% of the cases. Our aim was to study the clinical outcome of Diisocyanate-induced asthma. A questionnaire was sent to the 235 patients alive in 1995, and validated by reexamining clinically 91 of them. The study was carried out on average 10 () yr after the diagnosis. Of the patients 82% experienced symptoms of asthma, 34% used no medication, and 35% were on regular medication. The patients having displayed immunoglobulin E (IgE) antibodies to isocyanates used less medication (OR 0.273; CI 0.098, 0.758) and had fewer symptoms of asthma (OR 0.329; CI 0.124, 0.875) than the IgE-negative ones. They also had a significantly shorter duration of symptoms (p = 0.0025), latency period (p = 0.0249), and duration of exposure (p = 0.0008) than the IgE-negative patients. This did not, however, entirely explain the more favourable outcome of the IgE-positive patients. Patients with HDI-induced asthma used less medication (OR 0.412; CI 0.229, 0.739) than patients with MDI- and TDI-induced asthma. The results confirm the generally rather poor medical outcome of Diisocyanate-induced asthma; the persistence of symptoms and unspecific bronchial reactivity were pronounced in TDI-induced asthma. A more favourable outcome was associated with IgE mediation and HDI inducement.
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long term follow up of hexamethylene Diisocyanate diphenylmethane Diisocyanate and toluene Diisocyanate induced asthma
American Journal of Respiratory and Critical Care Medicine, 2000Co-Authors: Paivi Piirila, Helena Keskinen, Henrik Nordman, Ritva Luukkonen, Suvipaivikki Salo, Timo Tuomi, M TuppurainenAbstract:In 1976–1992 245 new cases of asthma induced by Diisocyanates were diagnosed, caused by hexamethylene Diisocyanate (HDI) in 39%, diphenylmethane Diisocyanate (MDI) in 39%, and toluene Diisocyanate (TDI) in 17% of the cases. Our aim was to study the clinical outcome of Diisocyanate-induced asthma. A questionnaire was sent to the 235 patients alive in 1995, and validated by reexamining clinically 91 of them. The study was carried out on average 10 (3-19) yr after the diagnosis. Of the patients 82% experienced symptoms of asthma, 34% used no medication, and 35% were on regular medication. The patients having displayed immunoglobulin E (IgE) antibodies to isocyanates used less medication (OR 0.273; CI 0.098, 0.758) and had fewer symptoms of asthma (OR 0.329; CI 0.124, 0.875) than the IgE-negative ones. They also had a significantly shorter duration of symptoms (p = 0.0025), latency period (p = 0.0249), and duration of exposure (p = 0.0008) than the IgE-negative patients. This did not, however, entirely explai...
Adam V Wisnewski - One of the best experts on this subject based on the ideXlab platform.
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Recent developments in Diisocyanate asthma.
Annals of allergy asthma & immunology : official publication of the American College of Allergy Asthma & Immunology, 2020Co-Authors: Adam V WisnewskiAbstract:To summarize the latest experimental findings on Diisocyanate asthma and discuss the impact of these data on our understanding of disease pathogenesis and diagnosis. The literature reviewed includes articles from PubMed (National Library of Medicine) published within the last 3 years (1999-2001). In addition, pertinent older references are discussed to provide a historical perspective and background. The data discussed were chosen to highlight key concepts relevant to Diisocyanate asthma pathogenesis and are grouped accordingly. In many ways, Diisocyanate-induced asthma mirrors allergic asthma caused by other stimuli; however, the immune-mediated pathways believed to be central to the disease have been difficult to define. Recent studies on the human immune response to Diisocyanates provide additional evidence supportive of an immune basis for pathogenesis but also highlight well-recognized differences between Diisocyanate asthma and common atopic asthma. Studies on the antigenic form of Diisocyanates and their interaction with epithelial tissues provide new insights that may help explain these apparent immunologic differences. Genetic factors that influence disease have begun to be identified but remain poorly characterized. Associations of particular major histocompatibility complex class II alleles with Diisocyanate asthma further fuel the hypothesis that immune-dependent mechanisms underlie pathogenesis, whereas associations of glutathione S-transferase polymorphisms (in conjunction with recent studies defining the effects of Diisocyanates on thiol-redox homeostasis) may implicate additional antigen-independent mechanisms. Long-term follow-up studies of Diisocyanate asthma patients have confirmed the prognostic value of early removal of symptomatic patients from exposure and highlight the need for effective diagnostic tests of sensitivity and susceptibility. Diisocyanate-induced asthma appears to be a multifactorial disease involving the immune system, airway epithelium, and genetic factors. The potential long-term adverse effects of Diisocyanate exposure in sensitized patients underscore the need for further studies to elucidate the pathogenesis of this disease and identify biomarkers for sensitization and susceptibility.
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Recent developments in Diisocyanate asthma
Annals of Allergy Asthma & Immunology, 2003Co-Authors: Adam V WisnewskiAbstract:Objective To summarize the latest experimental findings on Diisocyanate asthma and discuss the impact of these data on our understanding of disease pathogenesis and diagnosis. Data Sources The literature reviewed includes articles from PubMed (National Library of Medicine) published within the last 3 years (1999-2001). In addition, pertinent older references are discussed to provide a historical perspective and background. Study Selection The data discussed were chosen to highlight key concepts relevant to Diisocyanate asthma pathogenesis and are grouped accordingly. Results In many ways, Diisocyanate-induced asthma mirrors allergic asthma caused by other stimuli; however, the immune-mediated pathways believed to be central to the disease have been difficult to define. Recent studies on the human immune response to Diisocyanates provide additional evidence supportive of an immune basis for pathogenesis but also highlight well-recognized differences between Diisocyanate asthma and common atopic asthma. Studies on the antigenic form of Diisocyanates and their interaction with epithelial tissues provide new insights that may help explain these apparent immunologic differences. Genetic factors that influence disease have begun to be identified but remain poorly characterized. Associations of particular major histocompatibility complex class II alleles with Diisocyanate asthma further fuel the hypothesis that immune-dependent mechanisms underlie pathogenesis, whereas associations of glutathione S-transferase polymorphisms (in conjunction with recent studies defining the effects of Diisocyanates on thiol-redox homeostasis) may implicate additional antigen-independent mechanisms. Long-term follow-up studies of Diisocyanate asthma patients have confirmed the prognostic value of early removal of symptomatic patients from exposure and highlight the need for effective diagnostic tests of sensitivity and susceptibility. Conclusions Diisocyanate-induced asthma appears to be a multifactorial disease involving the immune system, airway epithelium, and genetic factors. The potential long-term adverse effects of Diisocyanate exposure in sensitized patients underscore the need for further studies to elucidate the pathogenesis of this disease and identify biomarkers for sensitization and susceptibility.
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Mouse Models of Diisocyanate Asthma
American Journal of Respiratory Cell and Molecular Biology, 2002Co-Authors: Carrie A Redlich, Adam V Wisnewski, Terry GordonAbstract:Occupational asthma is the most commonly reported ocpriate forms and concentrations of Diisocyanates for use in animal models and in vitro studies. cupational lung disease in many industrialized countries. Diisocyanates, highly reactive low molecular weight comClinical Presentation of Diisocyanate Asthma pounds used to make polyurethanes, are the most commonly identified cause of occupational asthma (1). Animal Clinically, the presentation of Diisocyanate asthma can be and clinical studies of Diisocyanate asthma have been more variable and difficult to distinguish from adult onset asthma limited compared with atopic asthma, and our understanddue to other causes. There is a latency period between ing of Diisocyanate pathogenesis is less clear. Unlike typical exposure and onset of symptoms; patients develop respiraallergens that cause asthma, Diisocyanates are extremely tory symptoms after recurrent exposures over months to a reactive compounds, creating great uncertainty regarding few years. Once sensitized, individuals can develop early, the carrier proteins for these chemical haptens in vivo. Redelayed, or dual asthmatic attacks in response to very low search on Diisocyanate asthma has been hampered by this levels of exposure, making control difficult. Disease can uncertainty, as well as the lack of mouse models that replipersist away from exposure, emphasizing the importance cate the human disease. Recent studies have made signifiof early diagnosis (6, 7). It is estimated that 5%–15% of cant progress tackling both of these difficult problems. In exposed workers develop asthma (8, 9). However, exposure the present issue of AJRCMB, Matheson and colleagues and host risk factors are not well understood. Unlike many (2) investigate the role of tumor necrosis factor (TNF)types of asthma, atopy is not a risk factor for Diisocyanatein a mouse model of toluene Diisocyanate (TDI) asthma. induced disease. Certain human leukocyte antigen alleles This Perspective will discuss these findings and address key and glutathione S-transferase haplotypes have been associissues that have hindered progress in understanding diisocyated with Diisocyanate asthma, but this has not been conanate asthma and in developing better diagnostic tools. firmed (10–12). Several other recent promising mouse models that should The diagnosis of Diisocyanate asthma remains quite facilitate future research are also discussed. problematic and a challenge for physicians. Clinical history, The major Diisocyanates currently in use are diphenylquestionnaires, and physiologic studies frequently are not definitive (13, 14). Immunologic tests, although of great methane Diisocyanate, toluene Diisocyanate, and hexamethinterest, have shown variable correlation with disease. The ylene Diisocyanate (HDI) (Figure 1). The characteristics of prevalence of Diisocyanate-specific IgG and IgE antibodies Diisocyanate exposure that determine risk are unclear. Both among individuals with Diisocyanate asthma is variable and the respiratory tract and skin are considered important not closely associated with disease (13–18). Diisocyanateroutes of exposure and sensitization (3, 4). Depending on specific lymphocyte proliferation or cytokine enhancement the specific Diisocyanate, exposures can occur as an aerosol have also been investigated, but correlation with disease and/or as a vapor, as well as different monomeric and polyhas been variable (19–21). A promising study by Bernstein meric species, making airborne monitoring difficult (5). This and colleagues recently reported that monocyte chemoatcomplexity of exposure, along with the marked chemical tractant protein-1 (MCP-1) in vitro production had a sensireactivity, greatly adds to the difficulty of generating approtivity and specificity of 79% and 91% in diagnosing Diisocyanate asthma (16). Specific inhalation challenge is considered the “gold standard” for diagnosis. However, such testing is (Received in original form August 26, 2002) neither 100% sensitive nor specific, nor is it readily available
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a novel mouse model of Diisocyanate induced asthma showing allergic type inflammation in the lung after inhaled antigen challenge
The Journal of Allergy and Clinical Immunology, 2002Co-Authors: Christina A Herrick, Adam V Wisnewski, Carrie A Redlich, Lan Xu, Kim BottomlyAbstract:Abstract Background: Exposure to Diisocyanates, a group of highly reactive, low-molecular-weight compounds, is a major cause of occupational asthma. In contrast to mouse models of atopic asthma, previous mouse models of Diisocyanate-induced asthma have failed to show lung inflammation with characteristics of human disease. Objective : Our goal was to establish a novel mouse model of Diisocyanate-induced asthma in which lung inflammation reminiscent of that seen in human asthma is generated after inhaled antigen challenge. Methods : BALB/c mice were epicutaneously sensitized to hexamethylene Diisocyanate (HDI) and then challenged with an HDI-protein conjugate administered by means of an intranasal droplet. Results : HDI sensitization resulted in development of contact hypersensitivity and HDI-specific antibody production. Most importantly, however, vigorous inflammatory responses with characteristics of human asthma were generated in the lung after inhaled HDI challenge. Challenge of sensitized, but not unsensitized, mice resulted in airway eosinophilia, mucus hypersecretion, and production of T H 1-type (IFN-γ) and T H 2-type (IL-4, IL-5, and IL-13) cytokines by lung inflammatory cells. Despite the mixed T H 1/T H 2 response induced by HDI sensitization, use of cytokine-deficient mice revealed that airway eosinophilia was mediated by T H 2 cytokines and not by IFN-γ. Conclusion : We report a novel mouse model of Diisocyanate-induced asthma that, in contrast to previous models, demonstrates antigen-induced lung inflammation with characteristics of human disease. This model will allow investigation of the immunopathogenesis of Diisocyanate-induced asthma and should provide insight into this common form of occupational disease. (J Allergy Clin Immunol 2002;109:873–8.)
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identification of human lung and skin proteins conjugated with hexamethylene Diisocyanate in vitro and in vivo
American Journal of Respiratory and Critical Care Medicine, 2000Co-Authors: Adam V Wisnewski, Ranjana Srivastava, Christina Herick, Ranulfo Lemus, Hilary Cain, Nadine Magoski, Kim Bottomly, Meryl H. Karol, Lan Xu, Carrie A RedlichAbstract:Diiisocyanates are asthma-causing chemicals used in the commercial production of polyurethane. We have previously shown that human lung epithelial cell proteins can become conjugated with hexamethylene Diisocyanate (HDI) and may be biologically important in Diisocyanate-induced asthma. The objective of this study was to identify specific human lung and skin proteins that become conjugated with Diisocyanate after in vitro and in vivo exposure. Following in vitro exposure of human airway epithelial cells (A549), keratin 18, the 78-kD glucose-regulated protein, trans-1,2-dihyrobenzene-1,2-diol dehydrogenase, and actin were identified as prominent Diisocyanate-conjugated proteins through use of a combination of immunocytochemical and mass spectrometric techniques. Following in vivo inhalation of an HDI aerosol, keratin 18 was also identified as the predominant Diisocyanate-conjugated protein in human endobronchial biopsy samples, whereas albumin was the predominant Diisocyanate-conjugated protein in bronchoal...