Differential responsiveness to irritant mixtures. Possible mechanisms.
Explore the source record for details and available documents.
Air Pollution, Indoor↗
Biomedical subjects
R Bascom
Publications and source records attributed to R Bascom.
Photoreceptor peripherin is the normal product of the gene responsible for retinal degeneration in the rds mouse.
Retinal degeneration slow (rds) is a retinal disorder of an inbred strain of mice in which the outer segment of the photoreceptor cell fails to develop. A candidate gene has recently been described for the rds defect [Travis, G. H., Brennan, M. B., Danielson, P. E., Kozak, C. & Sutcliffe, J. G. (1989) Nature (London) 338, 70-73]. Neither the identity of the normal gene product nor its intracellular localization had been determined. We report here that the amino acid sequence of the bovine photoreceptor-cell protein peripherin, which was previously localized to the rim region of the photoreceptor disk membrane, is 92.5% identical to the sequence of the mouse protein encoded by the normal rds gene. The differences between the two sequences can be attributed to species variation. Monoclonal antibodies were used with Western blot analysis to localize the wild-type mouse peripherin/rds protein to isolated mouse rod outer segments and to show that it, like bovine peripherin, exists as two subunits linked by one or more disulfide bonds. The relative amounts of peripherin/rds protein and rhodopsin in retinal extracts of normal and rds mutant mice were also compared. Identification of peripherin as the protein encoded by the normal rds gene and its localization to membranes of rod outer segments will serve as a basis for studies directed toward defining the role of this protein in the morphogenesis and maintenance of the outer segment and toward understanding the mechanism by which the rds mutation causes retinal degeneration.
Amino Acid Sequence↗
Differential susceptibility to tobacco smoke: possible mechanisms.
Explore the source record for details and available documents.
Acute Disease↗
Upper respiratory tract environmental tobacco smoke sensitivity.
Some patients report rhinitis symptoms after exposure to environmental tobacco smoke (ETS), but objective assessments of this response have been lacking. Furthermore, the mechanism of this response is unknown. We assessed the frequency of ETS-related symptoms by administering a questionnaire to 77 healthy nonsmoking young adults who were participating in an unrelated study. Of the subjects 34% (26 of 77) reported one or more rhinitis symptoms (congestion, rhinorrhea, or sneezing) following ETS exposure. We then exposed 10 historically ETS-sensitive (ETS-S) and 11 historically ETS-nonsensitive (ETS-NS) subjects to 15 min of clean air followed by 15 min of sidestream tobacco smoke (CO concentration of 45 parts per million). At selected time points during these procedures we recorded symptoms, posterior nasal resistance, and spirometry and performed nasal lavages. ETS-S but not ETS-NS subjects reported significant (p less than 0.01) increases in nasal congestion, headache, chest discomfort or tightness, and cough following exposure to sidestream tobacco smoke. Rhinorrhea symptoms were greater and more prolonged in ETS-S subjects compared to ETS-NS subjects. Significant (p less than 0.01) increases in perception of odor and in eye, nose, and throat irritation occurred in both study groups, but ETS-S subjects reported significantly more nose and throat irritation. No significant changes in posterior nasal resistance occurred in the ETS-NS group but a significant increase occurred in the ETS-S subjects, with the resistance rising from 3.8 +/- 0.5 cm H2O/L/s (mean +/- SE) preexposure to a peak of 8.0 +/- 2.7 cm H2O/L/s 20 min after completion of the smoke exposure (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
The upper respiratory tract: mucous membrane irritation.
Despite the widespread recognition that mucosal irritation is a cardinal feature of "sick-building syndrome," few data exist on the cause, natural history, or pathophysiology of upper respiratory mucous membrane irritation. The baseline prevalence of nasal symptoms among building occupants is often 20%, but in some studies it is as high as 50 to 60%. New techniques of nasal challenge and analysis of cells and mediators in nasal lavage fluid have proved useful in the assessment of rhinitis caused by antigens, cold air, and viruses, and these techniques are now being applied to the study the response to irritants. Human inhalation challenge studies have recently demonstrated a spectrum of sensitivity to environmental tobacco smoke, but the basis for this difference requires additional investigation. Animal and in vitro studies indicate that the chemosensitive neurons and airway epithelium may be critical targets for irritants that participate in the induction of inflammation. New research methods are needed, particularly to evaluate complaints of nasal congestion, drying, and irritation. Techniques should be developed that may be useful for field studies, where the health effects of a complex mixture are being assessed in a specific indoor environment. There exists a group of individuals who report a variety of symptoms on exposure to low levels of common volatile organic mixtures such as perfume, cigarette smoke, and cleaning agents. Some of these individuals report having occupied "sick buildings" during the time their symptoms began. Research is needed to understand the basis of their complaints, their etiology, and treatment.
Acrolein↗
Effect of intranasal capsaicin on symptoms and mediator release.
Differential nasal responsiveness to environmental tobacco smoke (ETS) has been documented in humans and we hypothesized that this reflects differential responsiveness to c-fiber stimulation. We compared the response to intranasal capsaicin in subjects with and without a history of ETS-rhinitis. We challenged 10 ETS-sensitive and 11 ETS-nonsensitive subjects intranasally with 25 mg of lactose powder followed by 25 pg to 25 ng of capsaicin in 25 mg of lactose. Subjects rated nasal symptoms and underwent nasal lavage. In each lavage, the concentrations of albumin (an index of vascular permeability), kinins and histamine (a marker of mast cell activation) were measured. Nasal lavage tosyl-L-arginine methyl ester (TAME)-esterase activity, which can be a reflection of mast cell activation, increased vascular permeability or glandular secretion, was also determined. Subjects with a history of ETS-rhinitis reported more rhinorrhea than subjects without a history of ETS-rhinitis (P less than .01). No significant increase occurred in nasal lavage histamine, albumin or kinins in either subject group. TAME-esterase activity (presumably a reflection of increased glandular secretion) increased greater than 1000 cpm in 12/21 subjects (designated "TAME-producers"), but this was unrelated to ETS-sensitivity. TAME producers showed a dose-dependent increase in TAME-esterase activity, whereas TAME nonproducers showed no change at any capsaicin dose. We conclude that capsaicin causes nasal symptoms and glandular stimulation without evidence of increased vascular permeability or mast cell activation. ETS-rhinorrhea symptoms in humans appear related to c-fiber stimulation. The absence of c-fiber-induced glandular secretion, although not related to ETS-sensitivity, was associated with decreased sneezing and increased symptoms of capsaicin-induced nasal burning.
Administration, Intranasal↗
Effect of ozone inhalation on the response to nasal challenge with antigen of allergic subjects.
The effect of oxidant inhalation on allergic illness is of interest because allergic patients often report increased respiratory symptoms during episodes of poor air quality, and epidemiologic studies demonstrate an association between increased levels of the air pollutant ozone and exacerbations of asthma. The purpose of this study was to characterize the upper respiratory response to ozone inhalation in asymptomatic, allergic subjects and to determine whether ozone pre-exposure increased the acute response to nasal challenge with antigen in these subjects. A group of 12 asymptomatic subjects with a history of allergic rhinitis were exposed in a randomized, cross-over design, at rest, on each of 2 days, separated by 2 wk, to 4 h of clean air or 0.5 ppm ozone in an environmental chamber. Following the exposure period, subjects underwent nasal challenge with four doses of antigen (1 to 1,000 PNU ragweed or grass). Symptoms were rated and nasal lavage performed after each dose. Measurement of histamine and albumin concentration and TAME-esterase activity and determination of cell counts and differentials were performed. Exposure to ozone caused significant increases in upper and lower respiratory symptoms, a mixed inflammatory cell influx with a sevenfold increase in naval lavage neutrophils, a 20-fold increase in eosinophils, and a tenfold increase in mononuclear cells, as well as an apparent sloughing of epithelial cells. There was a significant increase in nasal lavage albumin concentration on the ozone exposure day and a small increase in nasal lavage histamine concentration on both the ozone and clean air exposure days. TAME-esterase activity showed no significant increase overall, but increased at least twofold in 5 of 12 subjects. (ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Inhalation↗
Leukotriene B4 as a mediator of early and late reactions to antigen in humans: the effect of systemic glucocorticoid treatment in vivo.
The role played by leukotriene B4 (LTB4) in human allergic reactions has been the subject of recent interest and speculation. To characterize further the role of this mediator, we quantitated LTB4 levels in nasal washing by radioimmunoassay in 13 atopic subjects during immediate and late reactions after nasal antigen challenge while the subjects were taking placebo or prednisone (20 mg every 8 hours for 48 hours) in a double-blind, placebo-controlled, crossover protocol and compared these levels with levels of seven nonatopic subjects undergoing similar nasal antigen challenge. Nasal antigen challenge of atopic subjects resulted in an increase in LTB4 levels during the immediate reaction in 10 of 13 subjects (9/13 with a greater than 50% increase over baseline) with no similar increase observed in nonatopic subjects (p less than 0.05). An increase in LTB4 levels was observed in 12/13 atopic subjects (6/13 with greater than 50% increase over a second baseline) during late time periods (p less than 0.05), which was associated with an influx of neutrophils (from 65,000 +/- 43,000 to 1,246,000 +/- 829,000; p less than 0.05). However, nonatopic subjects appeared to demonstrate a similar late increase in LTB4 levels. High-performance liquid chromatography analysis of immunoreactive LTB4 demonstrated that 84% of immunoreactive LTB4 coeluted with the biologically isomer during the immediate reaction, whereas 44% to 61% coeluted with the biologically active isomer during late reactions. Steroid pretreatment had no effect on either the early or late increase in LTB4 levels or on the neutrophil influx observed during the late reaction.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Major basic protein and eosinophil-derived neurotoxin concentrations in nasal-lavage fluid after antigen challenge: effect of systemic corticosteroids and relationship to eosinophil influx.
The late-phase response to nasal challenge with antigen is associated with a mixed inflammatory cell influx in which the eosinophil demonstrates the earliest and greatest proportionate rise. We investigated the evidence for activation of the eosinophil during the late response by measuring the concentration of the eosinophil-derived mediator major basic protein (MBP) and the eosinophil-derived neurotoxin (EDN) in nasal-lavage fluids before and for 11 hours after antigen challenge in 13 subjects with seasonal allergic rhinitis. The subjects received oral prednisone (20 mg three times daily) or placebo in a double-blind, crossover manner for 2 days before each of two antigen challenges. After placebo pretreatment, significant increases over diluent baseline (4.5 +/- 0.4 ng/ml) occurred in the levels of MBP in nasal-lavage fluid during the early (9.8 +/- 2.9 ng/ml; p less than 0.005) and late (15.3 +/- 4.8 ng/ml; p less than 0.01) responses to antigen challenge. Significant increases (p less than 0.05) in the concentration of EDN also occurred during the late response to antigen that correlated with the levels of MBP (r = 0.48; p less than 0.001). The cumulative late-phase increase in MBP correlated closely (rs = 0.96; p less than 0.005) with the total influx of eosinophils. Oral prednisone pretreatment significantly reduced the mean of each subject's peak late-phase concentration of both MBP (30.7 +/- 5.8 ng/ml versus 13.3 +/- 4.3 ng/ml; p = 0.005) and EDN (885 +/- 659 ng/ml versus 71 +/- 41 ng/ml; p less than 0.05). These data provide evidence for eosinophil degranulation during the late response and inhibition of this response by prednisone, supporting its pathogenetic role.
Blood Proteins↗
Acute pulmonary response in healthy, nonsmoking adults to inhalation of formaldehyde and carbon.
Formaldehyde (HCHO) is a common chemical found in occupational and residential environments and has been suggested as a cause of asthmalike symptoms in some individuals. Clinical and animal studies suggest that HCHO adsorbed on respirable particles may elicit a greater pulmonary physiologic and inflammatory effect than gaseous HCHO alone. The purpose of this study was to determine if respirable carbon particles have a synergistic effect on the acute symptomatic and pulmonary physiologic response to HCHO inhalation. We randomly exposed 24 normal, nonsmoking, methacholine-nonreactive subjects to 2 h each of clean air, 3 ppm formaldehyde, 0.5 mg/m3 respirable activated carbon aerosol, and the combination of 3 ppm formaldehyde plus activated carbon aerosol. The subjects engaged in intermittent heavy bicycle exercise (VE = 57 l/min) for 15 min each half hour. Measures of response included symptom questionnaires, spirometry, body plethysmography, and postexposure serial peak flows. Formaldehyde exposure was associated with significant increases in reported eye irritation, nasal irritation, throat irritation, headache, chest discomfort, and odor. We observed synergistic increases in cough, but not in other irritant respiratory tract symptoms, with inhalation of formaldehyde and carbon. Small (less than 5%) synergistic decreases in FVC and FEV3 were also seen. We observed no HCHO effect on FEV1; however, we did observe small (less than 10%) significant decreases in FEF25-75% and SGaw which may be indicative of increased airway tone. Overall, our results demonstrated synergism, but the effect is small and its clinical significance is uncertain.
Administration, Inhalation↗
Effect of nitrogen dioxide exposure on susceptibility to influenza A virus infection in healthy adults.
The effect of NO2 exposure and human susceptibility to respiratory virus infection was investigated in a placebo-controlled, randomized, double-blind trial conducted in an environmentally controlled research chamber over 3 yr. Healthy, nonsmoking, young adult volunteers who were seronegative to influenza A/Korea/82 (H3N2) virus were randomly assigned to breathe either filtered clean air (control group) or NO2 for 2 h/day for 3 consecutive days. The NO2 concentrations were 2 ppm (Year 1), 3 ppm (Year 2), and 1 or 2 ppm (Year 3). Live, attenuated cold-adapted (ca) influenza A/Korea/82 reassortant virus was administered intranasally to all subjects immediately after the second exposure. Only one of the 152 volunteers had any symptoms; this person had a low grade fever. Pulmonary function measurements and nonspecific airway reactivity to methacholine were unchanged after NO2 exposure, virus infection, or both. Infection was determined by virus recovery, a fourfold or greater increase in serum or nasal wash influenza-specific antibody titers, or both. The infection rates of the groups were 12/21 (2 ppm NO2) versus 15/23 (clean air) in Year 1, 17/22 (3 ppm NO2) versus 15/21 (clean air) in Year 2, and 20/22 (2 ppm) and 20/22 (1 ppm) versus 15/21 (clean air) in Year 3. Each group exposed to 1 or 2 ppm NO2 in the last year became infected more often (91%) than did the control group (71%), but the differences were not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Cyclooxygenase metabolism of endogenous arachidonic acid by cultured human tracheal epithelial cells.
The epithelial cell may contribute to the regulation of pulmonary function during inflammatory diseases of the airways by producing metabolites of arachidonic acid (AA). We have used human tracheal epithelial cells (HTE), grown in serum-free medium, to examine cyclooxygenase metabolism of endogenous AA by these cells. Gas chromatography-negative ion mass spectrometry demonstrated that, regardless of stimulus (buffer, bradykinin, or the calcium ionophore A23187), epithelial cells produce PGE2 and PGF2 alpha but no detectable levels of PGD2, thromboxane B2, 6-keto-PGF1 alpha, or 9 alpha, 11 beta-PGF2. Preincubation of cultures with medium containing 5% human serum led to striking increases in the production of PGE2 and PGF2 alpha, regardless of stimulus. Concomitant with these increases in prostanoids, serum exposure caused a 3.6-fold increase in total cellular arachidonate. Arachidonate levels increased in all phosphoglyceride classes, with the greatest increases in phosphatidylethanolamine, phosphatidylcholine, and phosphatidylinositol. In serum-pretreated cells, PGE2 production was 1.46 +/- 0.12, 4.74 +/- 0.6, and 6.35 +/- 0.93 ng/10(6) cells (mean +/- SEM; n = 7) upon exposure to buffer, 10(-6) M bradykinin, and 1 micrograms/ml A23187, respectively, whereas PGF2 alpha levels were 1.53 +/- 0.22, 4.44 +/- 0.36, and 5.77 +/- 0.78 ng/10(6) cells, respectively. The response of HTE to bradykinin was dose-dependent (10(-8) to 10(-6) M) and was maximal within 5 min. We conclude that cyclooxygenase metabolism of endogenous arachidonate in HTE results in the specific production of PGE2 and PGF2 alpha. HTE in culture retain receptors for bradykinin and can be used to study lipid metabolism independent of other cell types.
Adult↗
Experimentally induced nasal allergic responses.
To investigate the pathogenesis of allergic rhinitis, we developed a nasal challenge model in which we examined the early, late, and rechallenge responses to antigen provocation. In these three aspects of the allergic reaction the physiologic responses are associated with inflammatory mediator release. Whereas the early response appears to be related mainly to mast cell activation and mediator release, the late reaction involves a different pattern of mediator release and an inflammatory cell influx, consisting of basophils, neutrophils, and eosinophils. Rechallenge with antigen 11 hours later results in an augmented immediate response. Pretreatment with aspirin reduces the levels of cyclooxygenase metabolites in nasal secretions without affecting the immediate physiologic response to antigen or the expected increase in the levels of histamine, N-alpha-tosyl-L-arginine methyl ester-esterase activity, and leukotriene C4. Pretreatment with systemic steroids does not affect the early allergic response, but significantly reduces mediator release during the late and rechallenge responses. The influx of eosinophils is inhibited by pretreatment with systemic steroids, but neutrophil influx is not. In contrast, pretreatment with topical steroids blocks the early response and the late and rechallenge responses. Influx of all cell types, including the neutrophil, was prevented. These studies show unequivocally that an inflammatory process follows the initial response to antigen and that this inflammation is affected by drugs important in the treatment of chronic allergic disease. We speculate that understanding allergic inflammation will lead to new therapeutic development.
Antigens↗
Studies on the allergic and nonallergic nasal inflammation.
Nasal lavage after antigenic and nonantigenic nasal stimulation has become an important tool for the study of inflammatory phenomena in the upper airway. Biochemical and cytologic information is relatively easily obtainable, and pharmacologic manipulations can be readily monitored. This article is of several studies aiming toward a more profound understanding of the mechanisms of allergic and nonallergic rhinitis by the use of laboratory-challenge procedures and nasal-lavage techniques. An early and a late reaction are detected clinically in the nose after antigen challenge of allergic individuals. In addition, the sensitivity to antigen significantly increases after the initial challenge, and this phenomenon is not obligatorily linked to the presence of a late-phase reaction (LPR). Inflammatory mediators, mostly mast cell- and/or basophil-derived, are detected in the nasal washes and correlate with the symptomatology in both the early and the late reactions. The allergen-induced LPR is marked by an early influx of eosinophils and, later, basophils and neutrophils. Elevation of major basic protein and histamine, but not prostaglandin D2, is detected during the LPR, giving evidence of active eosinophil and basophil participation. Systemic steroids can effectively suppress the clinical, biochemic, and cellular manifestations of antigen-induced LPR. Topical steroids have a similar effect but are also capable of suppressing the early reaction to antigen. A nonallergic form of rhinitis can be induced in the laboratory by nasal inhalation of dry air at freezing temperatures in individuals who report sensitivity to cold and windy environments.(ABSTRACT TRUNCATED AT 250 WORDS)
Environmental Exposure↗
The influx of inflammatory cells into nasal washings during the late response to antigen challenge. Effect of systemic steroid pretreatment.
Previous studies have demonstrated symptoms and mediator release occurring as long as 11 h after nasal challenge with antigen in selected allergic subjects. Pretreatment with systemic steroids reduced symptoms and mediators including histamine, TAME-esterase activity, and kinins. The aims of the present study were to characterize the cell influx during the late-phase response to antigen challenge and to determine the effect of pretreatment with systemic steroids on this response. We examined cytospin slides of nasal washings obtained before and hourly for 11 h after nasal antigen challenge in 10 asymptomatic allergic subjects with a history of seasonal rhinitis and 5 normal, nonallergic subjects. Allergic subjects received oral prednisone (20 mg 3 times a day) or placebo in a random, double-blind crossover manner for 2 days before each of 2 challenges 1 month apart. On placebo days, a mixed cell influx occurred in allergic subjects during the late response that was 50-fold greater than the cell influx in the nonallergic control subjects (p less than 0.005). During the first 3 h after antigen challenge, eosinophils (p less than 0.005), but not neutrophils or mononuclear cells, were observed. During the late phase (4 to 11 h), neutrophils, eosinophils, and mononuclear cells were all increased. Oral steroid pretreatment blocked the influx of eosinophils (p less than 0.005), but not that of other cells. These data demonstrate an inflammatory cell influx associated with the nasal late-phase response and suggest an important pathogenetic role for the eosinophil.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Eosinophilia, respiratory symptoms and pulmonary infiltrates in rubber workers.
This report describes a spectrum of respiratory illnesses associated with eosinophilia which occurred in a group of workers exposed to fumes from a synthetic rubber-based curing operation. Respiratory syndromes induced by this exposure included an acute sensitizing illness with dyspnea and wheezing in some workers and pulmonary infiltrates with eosinophilia in others. Another worker developed chronic obstruction of the airways with recurrent bronchitic illnesses. Mild to marked peripheral eosinophilia, up to 3,000/cu mm, was usually present in the symptomatic workers and in 11 of 30 asymptomatic workers. These cases illustrate the diversity of respiratory illnesses which may result from a common workplace exposure and reinforce the importance of considering occupational exposures in the differential diagnosis of peripheral eosinophilia.
Acute Disease↗
Basophil influx occurs after nasal antigen challenge: effects of topical corticosteroid pretreatment.
Both the pattern of mediator release during the late-phase response (LPR) and the reduction of the LPR with corticosteroid pretreatment have suggested that basophils, not mast cells, represent the main source of histamine in the late response to nasal antigen challenge. We tested this hypothesis by examining alcian blue-stained cytospin slides of nasal washings obtained before and for 11 hours after nasal antigen challenge in 11 asymptomatic subjects with seasonal allergic rhinitis. In a double-blind manner, subjects received placebo or topical flunisolide (50 micrograms, each nostril, twice daily) for 1 week before antigen challenge. One month later, the challenge was repeated with the alternate pretreatment. On placebo-treatment days, a twelve-fold increase occurred in the number and a threefold increase in the percentage of alcian blue-stained positive cells in nasal washings in the LPR compared to baseline. At least 68% of these alcian blue-stained positive cells were basophils, as determined by light microscopic criteria. Alcian blue-stained cell influx correlated with increases in histamine levels in nasal washes (p less than 0.001). Topical steroid pretreatment blocked the influx of alcian blue-stained positive cells, as well as other inflammatory cells, including eosinophils, neutrophils, and mononuclear cells. Symptoms and mediator release were also blocked. These data demonstrate an influx of basophils and suggest that these cells are responsible for the histamine release observed in the LPR. Our findings indicate that pharmacologic control of basophil histamine release may represent a strategy for the treatment of a variety of chronic allergic diseases that are believed to resemble the LPR.
Administration, Topical↗
Acute response to 3.0 ppm formaldehyde in exercising healthy nonsmokers and asthmatics.
Formaldehyde is an ubiquitous industrial and indoor air pollutant to which millions are daily exposed. Because of the paucity of scientific data concerning the inhalation toxicity of this compound in humans, we determined the symptoms and alterations in pulmonary function resulting from inhalation for 1 h of 3 parts per million formaldehyde in a controlled environmental chamber. The protocol consisted of randomized exposure of each subject to clean air or 3.0 ppm HCHO on 2 separate days. Twenty-two healthy normal subjects engaged in intermittent heavy exercise (VE = 65 L/min) and 16 asthmatic subjects performed intermittent moderate exercise (VE = 37 L/min). Symptoms and pulmonary function were assessed during the time course of exposure; nonspecific airway reactivity was assessed after exposure. Both groups exhibited similar, significant (p less than 0.01) increases in perceived odor, nose/throat irritation, and eye irritation throughout the exposure. The normal group had the following statistically significant (p less than 0.02) lower pulmonary functions after 55 min of exposure to formaldehyde as compared to clean air: 3.8% in FEV1, 2.6% in FVC, and 2.8% in FEV3. The asthmatic group showed no statistically significant decrements in pulmonary function. Five of 38 subjects studied had decrements in FEV1 greater than 10%. In conclusion, acute exposure to 3 ppm HCHO produced: consistent irritant symptoms in both normal and asthmatic subjects, small decreases in pulmonary function in normal subjects engaging in heavy exercise, and clinically significant responses (defined here as decrements in FEU1 greater than 10) in 13% of the study population.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗