Nonspecific Irritants Research Articles

Immunoregulatory Mechanisms Involved in Elicitation of Allergic Contact Hypersensitivity

At first sight, the pathophysiology of contact hypersensitivity (CHS) seems to be well understood. Whereas this may apply to some extent to the sensitization phase of CHS, very little is actually known about the elicitation phase of this response. Although the mechanisms of T-cell priming (sensitization) may be more interesting for immunologists, those involved in the elicitation of T cell-mediated secondary responses are more relevant for clinical management because clinically manifest allergic contact dermatitis always reflects the effector phase of CHS. This review summarizes the role of different cellular components and soluble mediators on the elicitation of CHS. In addition, recent studies revealed that, besides selective activation of antigen-specific T cells, epicutaneous application of haptens has a number of direct effects on the cutaneous immune system. The most relevant of these are induction of cytokine and chemokine secretion and endothelial activation. In an attempt to integrate data on this issue, it is proposed that the capacity of contact allergens to directly induce proinflammatory signals in the skin is of relevance and perhaps essential for elicitation of clinically manifest CHS responses. Moreover, the proinflammatory effect of allergens themselves may explain the strict dose dependency of CHS responses and the relatively high concentrations of allergens needed for elicitation of CHS because allergens evoke nonspecific irritation only when applied in relatively concentrated form.

Immunoregulatory mechanisms involved in elicitation of allergic contact hypersensitivity

At first sight, the pathophysiology of contact hypersensitivity (CHS) seems to be well understood. Whereas this may apply to some extent to the sensitization phase of CHS, very little is actually known about the elicitation phase of this response. Although the mechanisms of T-cell priming (sensitization) may be more interesting for immunologists, those involved in the elicitation of T cell-mediated secondary responses are more relevant for clinical management because clinically manifest allergic contact dermatitis always reflects the effector phase of CHS. This review summarizes the role of different cellular components and soluble mediators on the elicitation of CHS. In addition, recent studies revealed that, besides selective activation of antigen-specific T cells, epicutaneous application of haptens has a number of direct effects on the cutaneous immune system. The most relevant of these are induction of cytokine and chemokine secretion and endothelial activation. In an attempt to integrate data on this issue, it is proposed that the capacity of contact allergens to directly induce proinflammatory signals in the skin is of relevance and perhaps essential for elicitation of clinically manifest CHS responses. Moreover, the proinflammatory effect of allergens themselves may explain the strict dose dependency of CHS responses and the relatively high concentrations of allergens needed for elicitation of CHS because allergens evoke nonspecific irritation only when applied in relatively concentrated form.

Analysis of laser Doppler perfusion images of experimental irritant skin reactions.

Laser Doppler perfusion imaging (LDPI) permits measurement of skin blood flow changes in patch test reactions. It is, as yet, unclear how collected data can best be handled and presented in order to maximize the possible discriminatory advantage of the imaging technique and to make the selection of data for statistical analysis as objective as possible. The aim of the present study was to compare a new software program (LDISOFT) for the analysis of LDPI images with the built-in standard statistical functions in the LDPI system (PIM 1.0). In addition, a modification of the software was used to gather additional data by performing sequential perfusion images. A dithranol cream was applied under Finn chambers for 30, 60 and 90 min on the ventral forearm skin of three volunteers. Photographic documentation and LDPI recordings were performed immediately after the removal of the Finn chambers and at 24, 48, 72 and 96 h. By the use of the above mentioned software, rectangular and threshold selected regions of interest were used to find an optimal way of calculating the mean perfusion and extent of the reactions. An LDISOFT threshold of 2 V was adequate and showed agreement (r<0.902, n=78) between mean perfusion analysis performed by LDISOFT (threshold-steered region of interest) and LDPI statistics (rectangular region of interest). The LDISOFT program had the added advantage of comparing application-site size with reaction size. Sequential recordings showed both spatial and temporal perfusion variability. Utilization of the full potential of LDPI will involve optimization of data analysis and presentation. A more "automated" system for data analysis will reduce bias due to subjective selection of analysis area. Particularly in weaker reactions, in irregular shaped or ring reactions and when there is non-specific background irritation, this may represent an advantage. Averaging of sequential recordings reduced background noise.

Work-related asthma in a population exposed to grain, flour and other ingredient dusts.

The purpose of the study was to determine the prevalence and causation of work-related asthmatic symptoms in a population exposed to grain, flour and other ingredient dusts. Where workers complained of asthmatic symptoms which were the result of dust exposure, follow-up aimed to identify whether the symptoms were the result of sensitisation or of non-specific irritation. A questionnaire was presented to 3,450 workers who had exposure to dust during the course of flour milling (528), bread baking (1,756), cake baking (209) and other activities in food preparation (957). Those with positive responses were followed-up by taking a formal history, examination, skin prick testing and serial peak flow measurement. The overall prevalence of work-related asthmatic symptoms was 4.4% (153 out of 3,450). In the group who were followed-up (128 out of 153), non-specific respiratory irritation was thought to be the cause in 90 (2.6%), whilst sensitisation was responsible for symptoms in 12 (0.3%). Of the 12 cases due to sensitisation, the agents responsible were: fungal amylase (10 cases, all associated with bread baking), flour (one case, associated with flour packing), and grain (one case, associated with flour milling). Non-specific irritation is considerably more common than sensitisation as the cause of work-related asthmatic symptoms in flour milling, baking and other flour-based industries. The prevalence of sensitisation to flour is very low (less than 1 in 1,000) in all these industries. The principal sensitiser encountered in modern plant bakeries appears to be fungal amylase. The most important source of exposure to fungal amylase is probably the debagging, sieving, weighing and mixing of bread improvers.

Topical retinoic acid for photoaged skin: Therapeutic effects and mechanisms

Topical all-trans-retinoic acid actively repairs photoaged skin. Roughness is the first parameter to show improvement, and is related to epidermal hyperproliferation, compaction of the stratum corneum and increase in epidermal glycosaminoglycans. Lightening of hyperpigmented lesions is correlated with a reduction in epidermal melanin content. Reduction in wrinkling occurs later, and is probably related to deposition of new collagen in the upper dermis. Epidermal atypia and dysplasia are also improved. Side-effects of dryness, peeling, erythema and irritation are dose-dependent, and diminish with continued treatment. The extent of the role of non-specific irritation, if any, is yet to be determined. Specific nuclear retinoid receptors exist, and are present in skin. Within the nucleus the vitamin - receptor complex binds to specific DNA sequences - response elements - situated in specific retinoid target genes, thereby regulating transcription of these target genes. The precise genes targeted by the retino...

Cytometric profile of molybdenum-induced contact sensitization versus a strong allergen reaction to oxazolone in murine auricular lymph node (ALN) test

Induction of contact hypersensitivity (CH) by molybdenum chloride (MoCl 5) was determined by auricular lymph node (ALN) test in C57B1/6 mice. The ALN test was further improved by immunophenotyping and cytometric analysis of subset-specific cells in the draining node. Skin sensitization was induced by topical ear exposure to 1.0–5.0% oxazolone and resulted in a strong dose-related ALN reaction. Analogous exposure to MoCl 5 resulted in a weaker but marked dose-related reaction, also manifested as an increase in cell number/ALN. Other differences between the oxazolone-induced strong sensitization and the MoCl 5-related ALN reaction were: (1) an increase in the total number of Ig + cells, which was, however, unchanged in the MoCl 5-exposed mice; (2) a significant increase in the total number of large/activated T-cell subsets; and (3) a marked shift in the relative percentage of gated large/activated subsets of ALN cells, which was not observed in the MoCl 5-exposed animals. Thus, it appeared that the molybdenum exposure induced a nonspecific increase in the cell number/ALN and was not accompanied by any marked activation of the T-cell subsets. Immunotoxicity of a 14 day subchronic exposure to MoCl 5 at 1–100 ppm in food was studied by quantification of splenic humoral IgM response to sheep erythrocytes (SRBC). Plaque-forming cells (PFC) and enzyme-linked immunosorbent assay (ELISA) revealed unchanged humoral exposure in MoCl 5-exposed mice. Cytometric assay of fluorescent beads uptake showed unchanged phagocytic activity of peritoneal macrophages from the MoCl 5-exposed mice. Immunophenotyping of CD4 +, CD8 +, Thy 1.2 + and Ig + cells revealed no effect of MoCl 5 exposure on the total count of cell subsets in the ungated populations of spleen, lymph nodes and peripheral blood cells. Molybdenum chloride should thus be considered as a non-immunotoxic and a weak, nonspecific contact irritant.

Morbidity, medication and trigger factors in a community sample of adults with asthma.

To determine asthma morbidity, use of medications and trigger factors for asthma attacks in an adult community sample. Follow-up questionnaires were sent to respondents indicating a history of asthma or any respiratory symptom on a screening questionnaire. A new scale to measure asthma severity was developed. Questionnaires were returned by 74% (589/795). Respondents with diagnosed asthma had more frequent symptoms and more disruption to lifestyle than those with non-specific respiratory symptoms. Inhaled beta-agonist and oral theophylline preparations were used by 61% and 16% of asthmatics, respectively. Preventive medications such as inhaled corticosteroids and cromoglycate were used daily by only 15% and 4%, respectively. The most frequently reported trigger factors were viral upper respiratory tract infections, cigarette smoke, house dust, smog and other non-specific irritants. Twenty per cent of asthmatics reported occupational exacerbation of symptoms. There is substantial morbidity from asthma in Victorian adults, which could be reduced by greater use of preventive medications, avoidance of trigger factors, peak flow monitoring and action plans. The asthma severity scale proved to be reliable and valid.

Host susceptibility to indoor air pollution

Host susceptibility to indoor air pollution

Role of 1,25-dihydroxyvitamin D3 in the generation of the acute-phase response in rats with talc-induced granulomatosis.

Subcutaneous injection of nonspecific irritants such as magnesium silicate (talc) provokes granulomatous inflammation in the rat. Part of the acute phase response (APR) in these animals is the loss of trabecular bone at sites distant from the site of inflammation. To assess the possible involvement of vitamin D in the bone loss, we studied the development of the acute phase response in vitamin D-deprived rats. The serum APR provoked by subcutaneous inflammation in rachitic rats consisted of hypozincemia, hypercupremia, increased alkaline phosphatase activity and adrenocorticotropic hormone (ACTH) concentration, and was similar to that in control animals except for the absence of hypoferremia. Control rats with talc-induced subcutaneous inflammation also had splenomegaly and decreased total and mononuclear peripheral blood cell counts, while subcutaneous inflammation did not induce spleen changes in rachitic rats. Subcutaneous inflammation induced the loss of trabecular bone and decreased the osteoblastic cell count in tibial metaphyses in control animals. Rachitic rats had abundant osteoid on trabecular surfaces, and the number of osteoblasts and osteoclasts was comparable to that of the controls. Subcutaneous inflammation did not affect any of the bone parameters in rachitic rats. These results indicate that vitamin D plays an important role in the generation of the acute phase response during inflammation, particularly in the induction of spleen and bone cell changes. The discrepancy of the blood on one hand and bone and spleen indices of the APR on the other, indicate that they may be divergent pathways in the generation of the inflammatory response, some of which may be dependent on vitamin D.

Morbidity among municipal waste incinerator workers

Objective: The present study investigated the olfactory function in workers exposed to moderate airborne cadmium (Cd) levels, with the purpose of identifying possible early adverse effects of the metal, not demonstrable with the traditional diagnostic methods. Methods: The exposed group consisted of 33 men employed in cadmium fusion, sintering and alloys lamination. Two reference groups were considered: the first consisted of 39 subjects assigned to manual workings, but not exposed to harmful substances for olfaction (drivers, warehousemen); the second was characterized by 23 subjects exposed to iron and steel welding fumes (iron base alloys), non-specific irritants on the respiratory tract. Olfactory threshold and odor identification ability were separately quantified. Individual occupational exposure was studied by calculating the mean blood and urinary cadmium values (CdB and CdU, respectively) of the five years period during which, for each worker, the highest levels of dose indicators were measured. As indicator of renal tubular damage, urinary β2-microglobulin levels in the same quinquennium were monitored. Results: Mean olfactory threshold scored significantly higher in Cd workers (−5.26 log10 v/v, P=0.02) than did in controls (welders: −5.78 log10 v/v; P=0.26 compared to non-exposed −6.37 log10 v/v). The odor identification test findings for Cd workers were similar to those of the reference groups. Moderate blood and urine cadmium levels (mean CdB 3.7 μg/l; mean CdU 4.4 μg/g creatinine) accompanied threshold impairment. Olfactory threshold weakening was confirmed in the subgroup of Cd workers in which urinary β2-microglobulin never exceeded 300 μg/l (−5.41 log10 v/v; P=0.045 compared to non-exposed). Conclusions: These data suggested that possible early toxic effects of the metal can occur at low levels, close to the limits proposed by the American Conference of Governmental Industrial Hygienists (ACGIH®), confirming the hypothesis that primary olfactory neuron may represent the early target for cadmium toxic action. The action of the metal seemed to be due to an elective tropism for the olfactory epithelium and not to a non-specific irritant effect on the nasal cavity. The mechanism of this effect did not appear linearly dose-related. These findings underline the importance of olfactory tests to identify the early effects of xenobiotics even at low-exposure levels, and to contribute to verify the adequacy of the current exposure limits.

Differential Regulation of Tyrosinase Activity in Skin of White and Black Individuals In Vivo by Topical Retinoic Acid

Tyrosinase activity is a key determinant of melanin production in skin. Because retinoic acid regulates tyrosinase activity in melanoma cells, we analyzed modulation of pigmentation in vivo by retinoic acid. Black and white subjects were either not treated, or treated topically for 4 d under occlusion with vehicle, retinoic acid (0.1%), or the irritant sodium lauryl sulfate (2%). In untreated skin, tyrosinase activity and melanin content were significantly greater (2.3 times, and 3.2 times, respectively) in blacks versus whites. Four days of treatment with topical retinoic acid did not alter tyrosinase activity or melanin content in black skin. In contrast, retinoic acid treatment significantly induced (2.7 times, n = 8) tyrosinase activity, compared to vehicle treatment, in white skin. Melanin content, however, remained unchanged at 4 d. In separate experiments, tyrosinase activity in white subjects (n = 25) was increased 16% (p = 0.01) in sodium lauryl sulfate-treated skin, and 77% (p = 0.0005) in retinoic acid-treated skin, compared to vehicle-treated skin. The effect of retinoic acid on tyrosinase activity could be differentiated from non-specific irritation, because tyrosinase activity in retinoic acid-treated skin was significantly greater (52%, p = 0.004) than sodium lauryl sulfate-treated skin. Similar results were obtained with the dihydroxyphenylalanine reaction done on vehicle, sodium lauryl sulfate-, and retinoic acid-treated white skin. Northern analysis (n = 6) and semi-quantitative polymerase chain reaction (n = 6) demonstrated that retinoic acid treatment did not alter tyrosinase mRNA levels in white skin. Western analysis revealed that induction of tyrosinase activity by retinoic acid also was not associated with increased tyrosinase protein content (n = 9), indicating that regulation of tyrosinase activity by retinoic acid occurs through a post-translational mechanism. These data demonstrate that low tyrosinase activity in white skin in vivo is retinoic acid inducible and high tyrosinase activity in black skin in vivo is neither further induced nor reduced by retinoic acid.

Stimulus-Selective Induction of CRABP-II mRNA: A Marker for Retinoic Acid Action in Human Skin

Acute topical treatment of human skin with retinoic acid (RA) results in a pleiotropic response, some aspects of which are mimicked by non-specific irritants. To identify reliable cutaneous markers of retinoid action, it is important to determine which aspects of this response are specifically due to the presence of RA. We have previously demonstrated a rapid and pronounced increase in steady-state cellular RA-binding protein II (CRABP-II)mRNA levels after topical RA treatment. Here we characterize the dose dependence and kinetics of this response, and compare the effects of a well-known irritant, sodium dodecylsulfate (SDS), to those of RA and its vehicle. The induction of CRABP-II mRNA in response to 0.1% RA cream was maximal by 16 h (elevenfold relative to untreated skin), and persisted at near-maximal levels (eight-fold) for up to 4 d. RA was potent in eliciting this response, as approximately half-maximal stimulation was observed after 16 h of treatment with 0.001% RA. Treatment for 4 d with 0.1% RA cream versus 2% SDS in RA vehicle resulted in nearly identical levels of cutaneous erythema, spongiosis, and epidermal thickening. However, the CRABP-II mRNA response to 2% SDS was no greater than that observed in response to vehicle alone (2.9 times relative to occluded skin control at 4 d). SDS also had no effect upon either CRABP-II or RAR-beta mRNA levels in quiescent human dermal fibroblasts in vitro, whereas RA elicited both responses at 1000-times lower concentrations than SDS. Taken together, these data identify the CRABP-II mRNA response as a reliable, rapid, and selective marker for retinoid activity in human skin.

Interpretation and Limitations of the Concept "Total Volatile Organic Compounds" (TVOC) as an Indicator of Human Responses to Exposures of Volatile Organic Compounds (VOC) in Indoor Air

The TVOC summation of masses of non-reactive substances has often been used as a practical way of reporting environmental measurements of volatile organic compounds. This total concentration, moreover, is often used as an indication of the potential of a multiomponent atmospheric pollution with substances of low chemical reactivity to cause chemically induced sensory irritation. This use of the TVOC indicator has never been standardized. Various authors have used different measuring techniques and the results have been used to predict certain types of health effect. This article discusses the toxicological background for the TVOC concept in relation to nonspecific sensory irritation and identifies some theoretical limitations in its use within this context. The TVOC indicator of nonspecific sensory irritations should be based only on a limited range of compounds and should be interpreted as a lower limit of the possible intensity of sensory irritation. Based on the discussions, some precautions are recommended with respect to measurements of TVOC and interpretation of the measurements.

Antigen-Specific IgG1-Mediated Epidermal Cell Injury: A Component of Contact Hypersensitivity Reactions in Guinea Pigs, Measurable In Vitro in Full-Thickness Skin Explants

Guinea pigs were sensitized by the topical application of either dinitrochlorobenzene (DNCB) or oxazolone on days 1, 2, 3, and 10. Seventeen days after the first treatment with the sensitizer, full-thickness 1.0-cm2 explants of untreated areas of skin were topically exposed in vitro to these contactants. Compared to the response of skin from control guinea pigs, skin from specifically sensitized animals showed a dose-related increase in the number of epidermal cells containing vacuoles. A specific increase in epidermal microblistering paralleled the increase in epidermal vacuolization. In addition, skin explants from sensitized animals (exposed to the contactant) showed a specific decrease in the incorporation of [14C]leucine. Full-thickness skin explants from unsensitized guinea pigs were sensitized in vitro by the intradermal injection of serum IgG1 fraction from oxazolone-sensitized guinea pigs. In such passively sensitized explants, the specific contactant produced an increase in the number of epidermal vacuoles, an increase in the amount of microblistering, and a decrease in the number of mast cells detectable by Giemsa staining. To elicit this specific response, the concentration of the specific contactant had to be mildly injurious, as well as antigenic. This requirement for nonspecific injury could be met by topically exposing skin explants to a nonspecific irritant followed by a sub-threshold concentration of the specific contactant. In contrast to vacuole formation and blistering, contactant-specific degranulation of mast cells (measured by the decrease in their number) did not require irritant levels of the contactant. These studies show that several components of contact sensitivity reactions can be reproduced in vitro by the passive transfer of sera containing antigen-specific immunoglobulins. Banks of such sera might, therefore, be useful in identifying (in human populations) many pre-existing sensitivities to chemical compounds.

In-situ striped bass (Morone saxatilis) contaminant and water quality studies in the Potomac River and upper Chesapeake Bay in 1989

In-situ striped bass contaminant studies were conducted in two important Chesapeake Bay spawning areas during the spring of 1989. The objectives of this research were to: (1) conduct three 96-h in-situ striped bass prolarval survival studies and one 27-day in-situ yearling survival study at three stations in the Potomac River during a major portion of the spawning season; (2) monitor 11 water quality parameters. 11 inorganic contaminants and 14 organic contaminants during the above experiments; (3) conduct three 96-h in-situ striped bass prolarval studies, one 14-day in-situ yearling test and one 27-day in-situ yearling test at three stations in the Upper Chesapeake Bay; (4) evaluate the water quality and contaminant conditions described in Objective (2) during these Upper Bay studies and (5) conduct histological and hematological examinations on surviving yearling striped bass tested in both the Potomac River and Upper Bay. Survival of prolarvae ranged from 3 to 33% in all three 96-h tests conducted in the Potomac River. Control survival was greater than 83%. Lowest prolarval survival was reported during the first experiment (less than 8%) when low water temperatures of 10 to 11°C were reported. These temperatures are stressful to prolarvae. Stressful conditions during the second and third experiments were not documented although 12 μg/l of arsenic was reported during experiment 3. Yearling survival during the 27-day in-situ test was 5% on the Maryland side of the river, 80% in the middle of the river and 30% on the Virginia side of the river. Control survival was 100%. Potentially stressful concentrations of chromium (29 μg/l) and arsenic (12 μg/l) were reported at the Virginia station (30% survival) during the yearling study. Stressful conditions were not documented at the Maryland station where survival was low (5%) or the middle river station where survival was high (80%). Survival of prolarvae at the three stations during Upper Chesapeake Bay tests ranged from 31 to 46% for experiment 1, 28 to 52% for experiment 2, and 6 to 22% for experiment 3. Control survival was 77% or greater. Prolarval survival during experiments 1 and 2 was considered good based on natural mortality that occurs with this life stage. The low survival during experiment 3 was likely related to the low temperatures of 10–11 °C reported during these tests. Survival of striped bass yearlings during the first 14-day yearling study ranged from 10 to 35% at the three field locations: control survival was 100%. This lest was conducted before the spawning season. Low water temperatures and temperature reductions of 7°C during short time periods were likely responsible for the reduced survival. Survival of yearlings during the 27-day yearling study (representing the spawning season) was greater than 98% al all stations. Control survival was 100%-. Although the survival of striped bass prolarvae and yearlings was generally good during these tests, it is important to note that various potentially toxic concentrations of metals (cadmium, chromium, copper and lead) were reported in the Upper Bay. The following insecticides were also reported after a major storm event in the Upper Bay between prolarval experiments 1 and 2: heptachlor epoxide ( 0.008 μg/l). edosulfan l(0.006 μg/l). dieldrin (0.005 μg/l) and 4.4-DDT (0.0014 μg/l). All contaminant concentrations were reported from composite samples: therefore, maximum values were likely much higher. Histological and hematological examinations of yearling striped bass exposed to Potomac River water suggested pathology that may be associated with water-borne contaminants. The following pathology was observed in these fish. PAS-positive inclusions of variable size and distribution in the hepatocytes of the liver, dilated kidney tubules and deposits of amorphous material near the glomerular arterioles and increased erythrocyte destruction resulting in hemoglobin in the liver and excessive accumulation and hemosiderin in the spleen. Pathology of yearlings exposed to Upper Chesapeake Bay water did not provide conclusive data to suggest the presence of contaminants. The condition of the gills from these nsh suggested a possible non-specific irritant in the water.

Factors determining development of allergy in infants.

For an infant to develop allergy (atopy), three main factors seem to be needed: genetic predisposition, allergen exposure, and contributory factors. The role of genetics seems to be mainly in transmitting a general atopic constitution and controlling the general IgE response. Together with environmental exposure, genetics possibly plays a role in determining the allergic shock organ and the specific offending allergen. Of the vast number of environmental allergens, food by far seems to be the major one in infancy, followed by indoor allergens then outdoor aeroallergens. Several intrinsic and extrinsic contributory factors can enhance the development of allergy, perpetuate its chronicity, or facilitate precipitation of symptoms. These factors can be immunologic defects, gastrointestinal diseases, infections, or nonspecific irritants such as tobacco smoke inhalation. Understanding all these factors is essential in formulating any program for allergy prevention in infants.

Environmental Control as a Modality of Management for the Pulmonary and Allergic Patient

Environmental control has been a subject frequently addressed in chapters or review articles in the medical literature on the management of allergic patients. The author's title often is "House Dust Eliminations." However, producing the optimal air for inhalation requries an understanding of not only the particulate components of allergens but also the particulate components of specific and nonspecific inhalant irritants, as well as the gaseous components allergens and irritants. This review addresses the health consequences to the pulmonary patient with mucocillary impairement and also the results of both allergen and irritant exposure in the allergic patient.

Control of Airway Caliber by Autonomic Nerves in Asthma and in Chronic Obstructive Pulmonary Disease

Autonomic nerves can influence airway caliber via their effects on airway smooth muscle, bronchial vessels, and mucous glands and may therefore contribute to airway narrowing in asthma or in chronic obstructive pulmonary disease (COPD). Human lungs receive cholinergic, noradrenergic, and peptidergic efferents and several types of afferents. Cholinergic nerve activity contributes to airway narrowing both in asthma and in COPD. Reflex vagal activity may be enhanced because of epithelial damage and exposition of sensory nerve endings to nonspecific irritants. Other possible mechanisms include defects in prejunctional receptors that inhibit acetylcholine release, several postjunctional factors that nonspecifically enhance the effect of a given degree of cholinergic muscle contraction on airway caliber, and interactions between inflammatory mediators and the cholinergic system. The main direct bronchodilating nerve activity in human lungs is nonadrenergic, and scanty data suggest that nonadrenergic inhibitory nerve activity may be variably reduced in asthmatics. Human airway muscle virtually lacks adrenergic innervation, but adrenergic nerves may influence airway caliber by acting on bronchial vessels, mucous glands, and parasympathetic nerves and ganglia. The response of asthmatic airways to beta-agonists seems intrinsically normal, but it may be reduced during severe asthma attacks. There are no convincing data that abnormal adrenergic control is present in the airways of patients with COPD. The physiologic relevance of excitatory neuropeptides in sensory nerves in human airways is uncertain. Tachykinins have proinflammatory and spasmogenic properties and are therefore of potential interest as a factor in the pathogenesis of obstructive airway disease. In conclusion, the data presently available support an abnormal autonomic control of the airways in asthma but not in COPD.

On the Mechanism of Antiinflammation Induced by Tumor Transplantation, Surgery, and Irritant Injection

Tumor transplantation, major surgery, and injection of nonspecific irritants elicit inflammation locally while suppressing inflammation induced subsequently and at distant sites. Such systemic antiinflammation in rodents occurs via corticosterone-independent and -dependent pathways. Based upon hormone measurements and the response to adrenalectomy, antiinflammation induced by irritants and certain surgical procedures is corticosterone independent while that which follows tumor transplantation is corticosterone dependent. However, injection of tumorous ascites stimulates both pathways since it contains two antiinflammatory factors: Factor A (molecular weight less than 2,000) does not alter hormone balance while Factor B (molecular weight 30,000-100,000) increases corticosterone levels and is corticosterone dependent. Desensitization of systemic antiinflammation develops rapidly regardless of whether it is corticosterone dependent (Factor B) or independent (Factor A or irritants). However, tumor transplantation resists desensitization possibly by inducing an immune response since lymphocytic mitogens prevent development of and break established desensitization. Nevertheless, abolition of tumor-induced antiinflammation follows injection of tumorous ascites by a mechanism that involves Factor B suppression of the corticosterone response to the tumor while Factor A apparently raises the threshold at which physiological increases in corticosterone inhibit leukocyte emigration. We conclude that systemic antiinflammation is a general consequence of a localized inflammatory reaction and that desensitization of such antiinflammation develops rapidly. Recent evidence indicates that certain mediators of inflammation are proinflammatory when administered intradermally but antiinflammatory when given intravenously. Thus, systemic antiinflammation may arise when chemical mediators of inflammation generated by a local reaction gain access to the circulation.

25 A comparison between antigen-induced leukocyte populations in the nasal mucosa and nasal secretions

25 A COMPARISON BETWEEN ANTIGEN-INDUCED LEUKOCYTE POPULATIONS IN THE NASAL MUCOSA AND NASAL SECRETIONS. M. Brown M.D, M.D.. M. Furin. M.D.. M. Taylor. MS, D.. Ba Marym We evaluated antigen-induced leukocyte influx into both the nasal mucosa and secretions. Eight seasonal allergic (A) and 11 nonallergic (NA) subjects underwent nasal lavage before (PRE), and lavage followed by biopsy 24 hours after, nasal antigen (ANT) challenge administered locally by a paper disc placed on one inferior turbinate. Biopsy of the site was performed immediately after the lavage in both groups. In addition, the allergic group underwent contralateral turbinate biopsy in the absence of antigen provocation at another time. Eosinophils (EOS), mononuclear cells (MONO) and neutrophils (PMN) were quantified in lavages and tissues. m MUCOSA (/mm2) A-PRE 18+13 hFlmQ E 2010+451 A-ANT *246+74 *3613+364 *89562 NA-ANT **48+37 2107+225 117:53 pgz (x103) EOS %P PMN 43+28 4732250 A-ANT 2222175 *46;18 553+180 NA-ANT *19.4 6435 **46+29 (Values represent means LSEM, *p<.O5, **p<.Ol, each, compared to the value directly above.) Allergies had more EOS than the NA in lavage, a finding not paralleled in the mucosa. After challenge, the tissue number of EOS, MONO and PMN increased significantly compared to unchallenged, but only the eos increased significantly compared to the NA. In fact, the PMN in NA-ANT were increased relative to the A-PRE, possibly reflecting nonspecific irritation caused by the placement of the antigen. Changes in cell counts did not correlate between the mucosa and the lavage. Part of the differences may relate to the small area challenged. We believe the mucosa and overlying mucus layer represent two interrelated, yet distinct, compartments.