Nonspecific Hyperresponsiveness Research Articles

Flowers and other trigger factors in asthma and rhinitis--an inquiry study.

Six hundred and eighty adult patients with asthma and/or rhinitis were questioned about symptoms elicited by 46 different flowers and 10 common non-specific environmental trigger factors listed in a questionnaire. Flowers or birch twigs were reported to elicit symptoms in 79% of the patients, somewhat more often in rhinitis than in asthma patients, and caused symptoms as often in non-atopics as in atopics. Birch twig and marguerite most frequently induced symptoms, followed by strongly smelling flowers such as hyacinth, lilac, and lily of the valley. Unspecific irritants caused symptoms in 98% of the asthmatics and in 67% of patients with rhinitis. Tobacco smoke and perfumes were the most important troublemakers. A significant positive correlation was found for elicitation of symptoms from flowers and from certain non-specific irritants. It is concluded that non-specific hyperreactivity as well as reaginic hypersensitivity are the mechanisms involved when birch twigs and flowers elicit symptoms.

Airway smooth muscle.

The greatest impetus to research in elucidating the fundamental biophysics and biochemistry of airway smooth muscle (ASM) has undoubtedly been provided by the need to understand how these are altered in asthma. Many of the biophysical and biochemical properties of this muscle have been reviewed before (Stephens, 1970; Stephens, 1977; Mulvaney, 1979; Souhrada and Loader, 1979; Stephens and Kroeger, 1980). They resemble those of striated muscle; however, even though mechanical properties are very similar, there are differences in biochemistry. For example, in smooth muscle, calcium-sensitive regulation of contraction is mediated by a calmodulin/myosin-light-chain kinase/phosphatase system, not by the familiar troponin-tropomyosin system (Gorecka et al., 1974; Mrwa and Ruegg, 1975; Dillon et al., 1981; Aksoy et al., 1982). Thus, the molecular mechanisms to be investigated in understanding disorders of increased smooth muscle contraction, which occur in allergic bronchospasm (Souhrada and Dickey, 1976), for example, may be quite different from those in striated muscle. Much of the following material is based on studies of canine tracheal smooth muscle (TSM) because there is evidence (Jenne et al., 1975) that it serves as a model for ASM-at least with respect to contractility down to the sixth generation of airways. Studies of isolated smooth muscle from smaller airways (Russell, 1978) are few and are based mainly on studies of lung strips (Lulich et al., 1976). Since then, we have developed a bronchial smooth muscle preparation (fifth generation) that allows precise study of those airways that are involved in allergic bronchospasm. Considerable work has been carried out on ASM from a variety of animal models of asthma. It should be pointed out that none of these reproduces the human disease exactly, and that they really should be identified as examples of nonspecific hyperreactivity. Be that as it may, the nonspecificity found in human patients in vivo and in animals (Peterson et al., 1971; Hargreave et al., 1980) suggests that the primary cause of asthma may reside at the muscle cell level. Whether it is the cell membrane, the excitation-contraction coupling apparatus, or the contractile machinery that is primarily involved, is not yet known with certainty.

Independent influence of reversibility of air-flow obstruction and nonspecific hyperreactivity on the long-term course of lung function in chronic air-flow obstruction.

We evaluated factors that might influence the course of lung function after 2 to 21 yr of follow-up in 81 nonallergic patients with chronic air-flow obstruction (CAO) and considerable lung function impairment (initial forced expiratory volume in one second as a percentage of inspiratory slow vital capacity (FEV1 % VC) ranging from 40 to 55% and increasing less than 15% after the administration of the anticholinergic bronchodilator thiazinamium). A more favorable rate of change in FEV1 was associated with less pack-years of smoking, less nonspecific hyperreactivity, and a higher degree of reversibility of air-flow obstruction, when expressed as the increase in FEV1 as a percentage of the predicted minus prebronchodilator FEV1 value. Nonspecific hyperreactivity and reversibility of air-flow obstruction appeared to influence the decline in FEV1 independently of baseline value of FEV1, both in smokers and ex-smokers. The hypothesis is put forward that regular bronchodilating therapy may be able to prevent deterioration of lung function. However, the possibility that interval therapy may ultimately produce the same results cannot be excluded. It seems to be important to stop smoking, both for the sake of its negative influence on the course of FEV1 and for the fact that a beneficial influence of bronchodilating therapy may become even more apparent.

Cold-induced bronchospasm in normal and sensitized rabbits

In anesthetized, paralyzed and artificially ventilated rabbits, changes in lung resistance induced by cooling the inspired air were studied under dry air conditions. Airway response to cold was measured in normal animals and in rabbits sensitized to bovine serum albumin. The magnitude of cold-induced bronchospasm was significantly greater in sensitized than in normal rabbits but the time course for recovery of control lung resistance during rewarming was the same in both groups and lasted longer than 4 min. Inhalation of a nebulized aerosol of sodium cromoglycate (SCG) markedly reduced cold-induced bronchospasm and shortened the recovery period, which then lasted only 20 to 30 sec. Vagotomy abolished the airway response to cold air in all cases and this was observed whether the vagnus nerves were cut before or after SCG inhalation. SCG or vagotomy exerted the same effect on the response to cold air in normal or sensitized rabbits. Sensitized animals showed an hyperresponsiveness to histamine as well as to cold air. These results suggest that cold-induced bronchospasm results from a vagally mediated reflex whose effects are only enhanced and prolonged by a local release of humoral factors, linked to the reflex path. The increased response to cold air in the sensitized rabbits seems to correspond to non-specific hyperresponsiveness of bronchial smooth muscle rather than to an increased local release of inflammatory mediators.

Cobalt-induced Bronchial Asthma in Diamond Polishers

Three diamond workers had occupational asthma attributed to the inhalation of cobalt powder. The exposure originated from high speed polishing disks with an abrasive consisting of microdiamonds cemented in extra fine cobalt not alloyed to tungsten carbide. The bronchoconstriction progressed towards the end of working-days; it was especially pronounced in the absence of an adequate exhaust ventilation; and it could be accompanied by rhinitis and chest tightness. Cobalt inhalation challenge tests were positive in all three patients, and exposure to cobalt temporarily increased nonspecific hyperreactivity.

8 - The Laboratory Investigation of Mediators and Inflammatory Cells in Asthma and Rhinitis

Many of the clinical and pathological features of asthma and rhinitis can be explained in part on the basis of the mode of action of various mast-cell associated mediators and associated agents as well as products derived from inflammatory cells. The methodology is now available for accurately identifying a number of preformed and newly-formed mediators in a variety of body fluids such as nasal secretions and the blood. Most of the studies to date have involved measurements of histamine and the high molecular weight neutrophil chemotactic activity whereas more recently assays for the lipoxygenase products, LTB 4 and LTC 4 , have been developed. In addition to specific allergen, non-specific stimuli such as exercise- and ‘fog’-induced asthma also appear to be associated with mediator release, suggesting that mediator cells such as mast cells respond to immunologic as well as non-immunologic triggers. Mediators can be broadly divided into agents which have a direct effect on bronchial tissue and those which recruit and activate secondary inflammatory cells. These cell types include neutrophils, eosinophils and mononuclear cells. Particular attention is given to the eosinophil as a major pro-inflammatory cell in asthma and possibly rhinitis. Equally, the macrophage may play a major role in the maintenance of the eosinophil-rich environment. The relationship between inflammation and non-specific hyperreactivity is also the subject of intense current investigation.

Occupational allergy to sunflower pollen

Although the sunflower belongs to the Compositeae family, allergy to sunflower pollen is not common. The occurrence of occupational allergy to this pollen species made it possible to characterize cross-reactive patterns of Compositeae pollens in a human experimental model. A 24-yr-old man developed rhinitis and conjunctivitis over 5 yr of exposure to sunflower pollens, and asthma developed during the fifth year. All respiratory and occular symptoms disappeared after he was removed from exposure, but he had a food allergic reaction while he was eating honey containing 30% sunflower pollens. The diagnosis of occupational allergy was based on history, skin prick tests and BAST to the pollen. Bronchial provocation tests performed after removal from exposure confirmed the sensitivity to sunflower pollens but there was no nonspecific hyperreactivity. It was found by RAST inhibition that sunflower pollen does not cross-react with other Compositeae pollens tested or with sunflower seed. The honey that elicited food intolerance was demonstrated to inhibit significantly sunflower pollen RAST.

The use of cromolyn in the management of hyperreactive airways and exercise

Cromolyn given a few minutes before exercise significantly protects from exercise-induced asthma in more than 70% of patients, probably through prevention of mediator release and possibly through other mechanisms. Its efficacy is comparable to that of theophylline, α-adrenergic blockers, and calcium channel blockers; better than that of atropine and ketotifen; but less than that of inhaled albuterol. Cromolyn seems to be more effective than metaproterenol and theophylline for prevention of late reactions of exercise-induced asthma. The addition of cromolyn markedly improved the results in patients not completely protected by inhaled adrenergic agents. Cromolyn also protects from other triggers like hyperventilation with cold air, ultrasonically nebulized water, and sulfur dioxide. Its prolonged administration causes a reduction in the nonspecific hyperreactivity as shown by tests of histamine inhalation or hyperventilation with cold air. This effect is thought to be a result of cromolyn's protection from allergic-induced increase in nonspecific hyperreactivity, although there is some evidence that it can also occur in nonatopic patients, sugesting a broader protective effect.

"Nonspecific" immunoenhancing T cells in tumor-bearing mice include anti-idiotypic subsets.

Splenocytes from DBA/2 mice inoculated 3 wk earlier with syngeneic P815 mastocytoma tumor cells produce increased numbers of antibody plaque-forming cells (PFC) when stimulated with either sheep red blood cells (SRBC) or phosphorylcholine (PC) on Streptococcus pneumoniae R36a in vitro. The nature of this nonspecific hyperreactivity was investigated in mixed cultures of purified splenic T and B cells. The addition of T cells from P815 tumor-bearing mice (TP815) into the cultures of normal B cells produced a significant enhancement of the PFC response to both SRBC and PC, when compared with the effect of normal T cells added to control cultures. The idiotypic profile of the enhanced anti-PC response was studied by a PFC-inhibition assay with monoclonal antibodies against two distinct idiotopic determinants (Id) of the T15 family. Normal B cells produced greater than 90% of T15 Id-positive (Id+) PFC. Addition of normal T cells diminished the proportion of T15 Id+ PFC to approximately 60%, whereas the rest of PFC were Id-. Addition of the immunoenhancing TP815 cells into the normal B cells cultures elevated the number of both T15 Id+ and Id- PFC responses, proportionally. However, when TP815 cells were first incubated on T15 protein-coated dishes and the non-adherent fraction was added to B cell cultures, the anti-PC PFC response remained enhanced but consisted of predominently T15 Id- PFC. These observations suggest that the early stage of P815 tumor growth activates various populations of specific helper/amplifier T cells including subsets with anti-idiotypic activity and that the generalized increase of antibody response to various antigens in tumor-bearing mice may be regarded as a polyclonal activation of specific T cells.

243 Therapeutic modification of non-specific hyperreactivity by sodium cromoglycate (SCG)

243 Therapeutic modification of non-specific hyperreactivity by sodium cromoglycate (SCG)

Vasoconstrictor hyperresponsiveness: An early pathogenic mechanism in the spontaneously hypertensive rat

Factors which play a primary role in the initiation and development of hypertension in sponstaneously hypertensive rats (SHR) are incompletely defined. To test the possibility that early changes in vascular function play a primary etiologic role, hindquarters of 3-week-old SHR and Wistar-Kyoto normotensive rats (WKY)_were perfused at constant flow with plasma substitute. The vasculature of SHR exhibited higher resistance to flow than that of WKY. The threshold constrictor response to norepinephrine (NE) was elicited at a significantly lower concentration (6×) than required in WKY, while threshold to BaCl 2 was not different. At concentrations of BaCl 2 above threshold, SHR exhibited marked hyperresponsiveness compared to WKY. This resulted in a greater maximum response and thus a steeper slope. The ED 50 for BaCl 2 was not different. A similar does—response relationship (greater maximu, steeper slope) was observed with NE except that the ED 50 as well as threshold was significantly lower in SHR than in WKY. These data show that vasoconstrictor hyperresponsiveness and increased vascular resistance are present at the time when the hypertension is first detectable. This hyperresponsiveness includes two distinct components: (1) A specific hypersensitivity to NE and (2) non-specific hyperresponsiveness which could derive from altered excitation—contraction coupling and/or from a structural mechanism already present when pressure difference begin to appear.

Pressor response to angiotensin II in hypertension: Correlation with plasma renin activity and response to norepinephrine and metaraminol

The pressor response to angiotensin II infused intravenously was studied in 8 normal subjects and 44 patients with primary and secondary hypertension. The mean dose of angiotensin II required to increase diastolic blood pressure by 20 mm. Hg was significantly lower in 24 patients with essential hypertension than in control subjects and 11 patients with renovascular hypertension. Mean plasma renin activity in peripheral venous blood was similar in control subjects and patients with essential hypertension and significantly higher in patients with renovascular hypertension. The pressor dose of angiotensin II was directly correlated with peripheral plasma renin activity. However, norrnotensive control subjects and patients with essential hypertension with similar values of plasma renin activity exhibited markedly different sensitivity to angiotensin II. Further, the pressor response to norepinephrine and metaraminol paralleled that to angiotensin both in patient groups and in individual cases. The results suggest that the pressor response to angiotensin II in hypertensive patients is related not only to the level of circulating endogenous angiotensin but also to nonspecific hyperreactivity in essential hypertension and nonspecific hyporeactivity in renovascular hypertension.