Clinical Bronchiolitis Obliterans Research Articles

85 - Immune Correlates from a Prospective Trial Suggest Leukotriene Signaling and Alternative Macrophage Activation in Clinical Bronchiolitis Obliterans Syndrome

85 - Immune Correlates from a Prospective Trial Suggest Leukotriene Signaling and Alternative Macrophage Activation in Clinical Bronchiolitis Obliterans Syndrome

Hyaluronan Contributes to Bronchiolitis Obliterans Syndrome and Stimulates Lung Allograft Rejection through Activation of Innate Immunity

Although innate immunity is increasingly recognized to contribute to lung allograft rejection, the significance of endogenous innate ligands, such as hyaluronan (HA) fragments, in clinical or experimental lung transplantation is uncertain. To determine if HA is associated with clinical bronchiolitis obliterans syndrome (BOS) in lung transplant recipients, and evaluate the effect of low- or high-molecular-weight HA on experimental lung allograft rejection, including dependence on innate signaling pathways or effector cells. HA concentrations were measured in bronchoalveolar lavage and plasma samples from lung recipients with or without established BOS. BOS and normal lung tissues were assessed for HA localization and expression of HA synthases. Murine orthotopic lung recipients with established tolerance were treated with low- or high-molecular-weight HA under varied experimental conditions, including Toll-like receptor (TLR) 2/4 and myeloid differentiation protein 88 deficiency and neutrophil depletion. HA localized within areas of intraluminal small airways fibrosis in BOS lung tissue. Moreover, transcripts for HA synthase enzymes were significantly elevated in BOS versus normal lung tissues and both lavage fluid and plasma HA concentrations were increased in recipients with BOS. Treatment with low-molecular-weight HA abrogated tolerance in murine orthotopic lung recipients in a TLR2/4- and myeloid differentiation protein 88-dependent fashion and drove expansion of alloantigen-specific T lymphocytes. Additionally, TLR-dependent signals stimulated neutrophilia that promoted rejection. In contrast, high-molecular-weight HA attenuated basal allograft inflammation. These data suggest that accumulation of HA could contribute to BOS by directly activating innate immune signaling pathways that promote allograft rejection and neutrophilia.

Respiratory Disease Among Flavoring-exposed Workers in Food and Flavoring Manufacture

Fixed airways obstruction was found in workers producing microwave popcorn in relation to inhaling synthetic butter flavoring volatiles in 2000. Since then, an industry-wide hazard of clinical bronchiolitis obliterans was found in other microwave-popcorn plants, in flavoring manufacture, and in diac

Effects of inhaled popcorn butter flavorings diacetyl, acetoin and acetic acid alone and in combination on airway reactivity to methacholine in rats

Inhalation of microwave popcorn butter flavoring induces clinical bronchiolitis obliterans in workers (“popcorn workers’ lung”). Diacetyl (D), a major component of many butter flavorings, is suspected as the primary etiologic agent. In rats, D inhalation caused marked damage in the respiratory epithelium. Acetoin (A) and acetic acid (AA) are also constituents of butter flavoring vapors and could contribute to toxicity of the mixture. Lung resistance (RL), dynamic compliance (Cdyn) and reactivity to methacholine (MCh) in terms of changes in RL and Cdyn, were measured in anesthetized rats 18 h after inhalation exposure to D, A and AA alone and in combination (D+A+AA). D (250 ppm) decreased basal RL and reactivity to MCh (RL); A (150 ppm) had no effect on basal values or reactivity to MCh; and AA (27 ppm) increased reactivity to MCh (RL). The mixed exposure (D+A+AA) increased basal Cdyn, decreased reactivity to MCh (RL), and increased the Cdyn response to MCh. Inhalation of lower flavoring concentrations [D (167 ppm) + A (118 ppm) + AA (18 ppm)], did not affect basal RL and Cdyn, but Cdyn responses to MCh were increased. The results indicate that A and AA neither mitigate or exacerbate D's effect on reactivity (RL), but inhalation of D+A+AA leads to more compliant lungs (Cdyn).

Obliterative bronchiolitis in lung allografts removed at retransplant for intractable airway problems

The role of large airway ischaemia, with resultant airway narrowing, in the development of post-lung transplant bronchiolitis obliterans has not been defined. A determination of clinical bronchiolitis obliterans syndrome (BOS), which is defined as a decline in FEV(1) from a stable post-transplant baseline, is difficult in the setting of airway complications. The aim of this study was to assess the evidence for histological bronchiolitis obliterans in lung allografts removed during retransplantation for severe recurrent airway narrowing. Case records and histological findings in allograft lungs removed at retransplantation were retrospectively reviewed. Five lung transplant recipients, who had undergone retransplantation because of severe recalcitrant airway stenosis, were identified. In each case, explant allograft lung pathology revealed evidence of bronchiolitis obliterans. There is a possible link between airway ischaemia, large airway stenosis and the development of bronchiolitis obliterans, which is the most common cause of death in lung transplant recipients after the first year. These findings may provide an impetus for evaluation of the role of bronchial artery revascularization techniques in the prevention of bronchiolitis obliterans.

Evaluation of the butter flavoring chemical diacetyl and a fluorochemical paper additive for mutagenicity and toxicity using the mammalian cell gene mutation assay in L5178Y mouse lymphoma cells

Diacetyl (2,3-butanedione) is a yellowish liquid that is usually mixed with other ingredients to produce butter flavor or other flavors in a variety of food products. Inhalation of butter flavoring vapors was first associated with clinical bronchiolitis obliterans among workers in microwave popcorn production. Recent findings have shown irreversible obstructive lung disease among workers not only in the microwave popcorn industry, but also in flavoring manufacture, and in chemical synthesis of diacetyl, a predominant chemical for butter flavoring. It has been reported that perfluorochemicals utilized in food packaging are migrating into foods and may be sources of oral exposure. Relatively small quantities of perfluorochemicals are used in the manufacturing of paper or paperboard that is in direct contact with food to repel oil or grease and water. Because of recent concerns about perfluorochemicals such as those found on microwave popcorn bags (e.g. Lodyne P208E ®) and diacetyl in foods, we evaluated both compounds for mutagenicity using the mammalian cell gene mutation assay in L5178Y mouse lymphoma cells. Lodyne P208E ® was less toxic than diacetyl and did not induce a mutagenic response. Diacetyl induced a highly mutagenic response in the L5178Y mouse lymphoma mutation assay in the presence of human liver S9 for activation. The increase in the frequency of small colonies in the assay with diacetyl indicates that diacetyl causes damage to multiple loci on chromosome 11 in addition to functional loss of the thymidine kinase locus.

Flavoring-related bronchiolitis obliterans

In 2000, inhalation of butter flavoring vapors was first associated with clinical bronchiolitis obliterans among workers in microwave popcorn production. Toxicologic and epidemiologic studies in the succeeding 5 years have intervention and research implications. Irreversible obstructive disease exists in workers throughout the microwave popcorn industry, in flavoring manufacture, and in the chemical synthesis of diacetyl, a predominant chemical in butter flavoring. Biologic plausibility of the role of diacetyl and other components of butter flavoring in causing bronchiolitis obliterans exists in rodent experiments which demonstrate respiratory epithelial necrosis. Some risky jobs were associated with short-term peak flavoring exposures, and average 8-h diacetyl exposures as low as 0.02 parts per million were measured in a work area where disease occurred in workers mixing butter flavorings with heated oil. Until safe levels of flavoring chemicals are determined, prevention requires substitution, engineering controls, improved work practices, and personal protective equipment to lower exposure, in conjunction with medical surveillance for accelerated declines in pulmonary function. An epidemiologic approach to longitudinal medical surveillance and flavoring chemical exposures, paired with inhalation toxicology studies of flavoring components, will lay the basis for determining health-protective exposure limits for various flavoring chemicals.

Popcorn worker's lung: In vitro exposure to diacetyl, an ingredient in microwave popcorn butter flavoring, increases reactivity to methacholine☆

Workers who inhale microwave popcorn butter flavorings experience decrements in lung function and can develop clinical bronchiolitis obliterans, i.e., "popcorn worker's lung" (Kreiss, K., Gomaa, A., Kullman, G., Fedan, K., Simoes, E.J., Enright, P.L., 2002. Clinical bronchiolitis obliterans in workers at a microwave-popcorn plant. N. Engl. J. Med. 347, 330-338.). In a rat inhalation model, vapors of an artificial butter flavoring damaged the epithelium of the upper and lower airways (Hubbs, A.F., Battelli, L.A., Goldsmith, W.T., Porter, D.W., Frazer, D., Friend, S., Schwegler-Berry, D., Mercer, R.R., Reynolds, J.S., Grote, A., Castranova, V., Kullman, G., Fedan, J.S., Dowdy, J., Jones, W.G., 2002. Necrosis of nasal and airway epithelium in rats inhaling vapors of artificial butter flavoring. Toxicol. Appl. Pharmacol. 185, 128-135.). Diacetyl, a butter flavoring component, is a major volatile ketone in the popcorn-processing workplace. We investigated the effects of diacetyl on epithelium of guinea pig isolated airway preparations and the effects of diacetyl in vitro on reactivity to bronchoactive agents. In the isolated, perfused trachea preparation, diacetyl added to the intraluminal (mucosal) bath elicited responses that began with contraction (threshold ca. 3 mM) and ended with relaxation. After a 4-h incubation with intraluminal diacetyl (3 mM), contractions to extraluminal (serosal) methacholine (MCh) were slightly increased; however, sensitivity to intraluminally (mucosally) applied MCh was increased by 10-fold. Relaxation responses of MCh (3 x 10(-7) M)-contracted tracheas to extraluminally applied terbutaline and intraluminally applied 120 mM KCl, to evoke epithelium-derived relaxing factor release, were unaffected by diacetyl. Exposure of the tracheal epithelium in Ussing chambers to diacetyl decreased transepithelial potential difference and resistance. These findings suggest that diacetyl exposure compromised epithelial barrier function, leading to hyperreactivity to mucosally applied MCh. The respiratory epithelium appears to serve as an initial target for the toxic effects of diacetyl in the airways.

Clinical bronchiolitis obliterans in workers at a microwave-popcorn plant.

In May 2000, eight persons who had formerly worked at a microwave-popcorn production plant were reported to have severe bronchiolitis obliterans. No recognized cause was identified in the plant. Therefore, we medically evaluated current employees and assessed their occupational exposures. Questionnaire responses and spirometric findings in participating workers were compared with data from the third National Health and Nutrition Examination Survey, after adjustment for age and smoking status. We evaluated the relation between exposures and health-related outcomes by analyzing the rates of symptoms and abnormalities according to current and cumulative exposure to diacetyl, the predominant ketone in artificial butter flavoring and in the air at the plant. Of the 135 current workers at the plant, 117 (87 percent) completed the questionnaire. These 117 workers had 2.6 times the expected rates of chronic cough and shortness of breath, according to comparisons with the national data, and twice the expected rates of physician-diagnosed asthma and chronic bronchitis. Overall, the workers had 3.3 times the expected rate of airway obstruction; those who had never smoked had 10.8 times the expected rate. Workers directly involved in the production of microwave popcorn had higher rates of shortness of breath on exertion and skin problems that had developed since they started work than workers in other parts of the plant. There was a strong relation between the quartile of estimated cumulative exposure to diacetyl and the frequency and extent of airway obstruction. The excess rates of lung disease and lung-function abnormalities and the relation between exposure and outcomes in this working population indicate that they probably had occupational bronchiolitis obliterans caused by the inhalation of volatile butter-flavoring ingredients.