Showing papers by "Robert M. Naclerio published in 1986"

Plasma kallikrein during experimentally induced allergic rhinitis: role in kinin formation and contribution to TAME-esterase activity in nasal secretions.

Abstract: We have shown recently that kinins are generated during experimentally induced allergic rhinitis in man, and have demonstrated that substrates for kinin-forming enzymes are provided during the allergic response by a transudation of kininogens from plasma into nasal secretions. In light of this increased vascular permeability during the allergic reaction, we have extended our studies on the mechanisms of kinin formation to examine the potential involvement of plasma kallikrein. Allergic individuals (n = 7) and nonallergic controls (n = 7) were challenged intranasally with an allergen, and nasal lavages, obtained before and after challenge, were assayed for immunoreactive human plasma kallikrein/prekallikrein (iHPK). Post-challenge iHPK values were significantly elevated (p less than 0.01) in the allergic group (353 +/- 394 ng/ml; x +/- SD) as compared to the nonallergics (19 +/- 22 ng/ml), and correlated with increases in kinins, histamine, and N-alpha-tosyl-L-arginine methyl esterase (TAME-esterase) activity and with the onset of clinical symptoms. Gel filtration studies revealed that plasma prekallikrein is activated during the allergic response and contributes to kinin formation prior to interaction with plasma protease inhibitors. We also show that the majority of the TAME-esterase activity detected in nasal secretions during the allergic response is due to activities consistent with a plasma kallikrein/alpha 2-macroglobulin complex and with mast cell tryptase.

Concentrations of glandular kallikrein in human nasal secretions increase during experimentally induced allergic rhinitis.

Abstract: We have previously demonstrated that a mixture of bradykinin and lysylbradykinin is generated in nasal secretions during the immediate allergic response to allergen. The present studies were performed to determine whether glandular kallikrein plays a role in kinin formation during the allergic reaction. Allergic individuals (n = 7) and nonallergic controls (n = 7) were challenged intranasally with appropriate allergen, and nasal lavages obtained before and after challenge were assayed for immunoreactive glandular kallikrein as well as for histamine, kinins, and N-alpha-tosyl-L-arginine methyl esterase (TAME-esterase) activity. The increase in postchallenge immunoreactive glandular kallikrein levels above baseline was significantly greater (p less than 0.01) for the allergic group (16.3 +/- 14 ng/ml; means +/- SD) than for the nonallergic controls (1.0 +/- 1.9 ng/ml). Increased levels of immunoreactive glandular kallikrein correlated with increases in kinins, histamine, and TAME-esterase activity and with the onset of clinical symptoms. Characterization of immunoreactive glandular kallikrein purified from postchallenge lavages by immunoaffinity chromatography confirmed the identity of this material as an authentic glandular kallikrein on the basis of its inhibition by protease inhibitors and by monospecific antibody to tissue kallikrein, its chromatographic behavior on gel filtration, and its ability to generate lysylbradykinin from highly purified human low m.w. kininogen. The specific activity of this purified material, in terms of kinin generation from kininogen, was very similar to that for authentic glandular kallikrein, suggesting that most if not all of the immunoreactive material purified from nasal lavages represented active enzyme. Inhibition studies by using pooled postchallenge lavages suggest that the majority of the kinin generating activity in these samples was due to glandular kallikrein. We conclude, therefore, that glandular kallikrein is secreted during the allergic response and can contribute to the formation of the lysylbradykinin produced during the allergic reaction.

Local generation of sulfidopeptide leukotrienes upon nasal provocation with cold, dry air.

Abstract: In order to assess whether sulfidopeptide leukotrienes are generated following nonimmunologic stimulation of inflammatory cells in vivo, 11 subjects complaining of symptoms of rhinitis when exposed to cold and dry environments were challenged by nasal breathing, first with warm, moist air and then with cold, dry air. Nasal lavages with normal saline were performed before and after each exposure. Immunoreactive leukotriene in the lavage fluids was significantly increased following cold, dry air exposure (2.6 ng/ml) compared with that after warm, moist air exposure (0.7 ng/ml) or at baseline (0.4 ng/ml) (p < 0.01 in both instances). Six more subjects, denying cold-air sensitivity, were subjected to the same protocol and had no mediator and symptom score changes after cold, dry air challenge. Leukotriene changes after cold, dry air were highly concordant with increments in histamine, prostaglandin D2,N-α-tosyl-l-arginine methyl ester (TAME) esterase(s) activity and symptom scores (p < 0.001). Separation of l...

Demonstration of inhibition of mediator release from human mast cells by azatadine base. In vivo and in vitro evaluation.

Abstract: In vitro experimentation using dispersed human lung mast cells demonstrated that azatadine base, a compound with known H1-antihistamine properties, inhibited anti-IgE-induced release of histamine and leukotriene C4by 45% and 85%, respectively. To assess the clinical relevance of these findings and to compare in vitro mast cell data with results obtained in vivo, nasally instilled azatadine was tested in a double-blind, placebo-controlled clinical trial in which nasal challenges with antigen were performed on eight allergic individuals. Pretreatment with azatadine significantly suppressed the number of sneezes following antigen challenge and inhibited the associated elevations in histamine, kinins, and enzyme(s) hydrolyzing the artificial substrateN-α-tosyl-L-arginine-methyl-ester in nasal secretions, whereas placebo was inactive. Hence, we showed agreement between our in vitro and in vivo experimental models of the allergic reaction. Topical application of azatadine base has the potential to become an effective antiallergic treatment. (JAMA1986;255:225-229)

Theophylline reduces histamine release during pollen-induced rhinitis

Abstract: In an attempt to understand how theophylline achieves its in vivo therapeutic effect, a double-blind crossover study of the effect of theophylline on the immediate response of the upper airways to challenge with antigen was performed. Ten subjects with allergic rhinitis were challenged with increasing doses of antigen extract, and their responses were assessed by counting the number of sneezes and measuring the level of histamine, N-alpha-p-tosyl-L-arginine-methyl ester-esterase activity, and kinin in nasal secretions. One-week premedication with theophylline led to serum levels in the therapeutic range (8 to 21 micrograms/ml). There were significant reductions in both the physiologic response to antigen challenge and the appearance of mediators in secretions after drug administration as compared to placebo. These data suggest that theophylline, at therapeutic blood levels, achieves at least part of its in vivo efficacy by reducing the release of histamine and other mediators from mast cells/basophils.

Inflammatory mediators in nasal secretions during induced rhinitis

Abstract: Introduction Studies dealing with nasal physiology in health and in disease are few in comparison with those dealing with pulmonary physiology. This discrepancy arises from the relative degree of morbidity associated with pathologic changes occurring in the upper as opposed to the lower airways. Although of less morbidity, the frequency of upper respiratory tract involvement is high. Allergic rhinitis affects approximately 15\"-;, ofthe population ofthe United States, and the common cold causes the greatest amount of absenteeism from school and work. Consequently, the study of nasal disease is important. Furthermore, since the nasal mucosa has many similarities with its counterpart in the lung, it is probable that an improved understanding of pulmonary physiology can be obtained by studying the more accessible nasal mucosa. This paper will review our work on the detection of inflammatory mediators in nasal secretions during induced nasal disease. It is hoped that the general reader will gain some additional insight into nasal disease, and that researchers will become motivated to study nasal physiology.

The pharmacologic control of mediator release from human basophils and mast cells.

Abstract: Insight into the pathogenesis of human allergic and inflammatory disorders has been obtained through a combination of in vitro and in vivo studies. These investigations have demonstrated that human ba

The role of kinins in human allergic disease.

Abstract: We have provided clear evidence that kinins are generated during local allergic reactions in man and have begun studies on the mechanisms by which kinins are formed during these reactions. Clearly, the extent to which kinins may contribute to the symptomatology of allergic rhinitis remains to be determined, but the levels of kinins detected in the model systems described above are sufficient to cause relatively profound physiologic effects. In addition to its ability to produce vasodilatation and edema, bradykinin has been reported to stimulate fluid production from airway submucosal glands via a reflex action and could function to increase mucus production and cause rhinorrhea. Kinins have also been shown to increase chloride transport in the airway and to stimulate the production of prostaglandin E2 by epithelial cells. Thus we believe kinins must now be considered as potentially important mediators in the pathogenesis of human allergic diseases.

Kinins as mediators of human allergic reactions.

Abstract: We have demonstrated that kinins are generated following nasal challenge with allergen of allergic (5.6 +/- 0.17 ng/m-), but not nonallergic (0.04 +/- .02 ng/ml), individuals (n = 8 in each case). The presence of kinin was highly correlated with that of histamine and TAME-esterase activity and with clinical symptoms (p less than 0.001). In a double blind, placebo-controlled study, topical administration of the drug Azatadine, which inhibits mast cell mediator release in vitro, reduced the clinical response to allergen challenge and reduced the concentrations of kinins, histamine, and TAME-esterase activity observed following allergen challenge. In addition to the immediate response to allergen, some individuals experience a recurrence of symptoms some 3-12 hours after challenge; in seven such individuals (13.5 +/- 3.2 ng kinin/ml in the immediate reaction), there was a second increase in nasal kinins (2.95 +/- 1.4 ng/ml) during this late reaction, again correlating with increases in histamine and TAME-esterase activity. HPLC analysis revealed that a mixture of bradykinin and lysylbradykinin is produced during both responses. Finally, 12 subjects with a history of nasal symptoms upon exposure to cold, dry air (CDA) were compared to five asymptomatic individuals in a nasal challenge system involving nasal breathing of CDA and warm, moist air (WMA). For the symptomatic group the levels of kinin in nasal lavages were significantly increased after CDA (2.9 +/- 0.8 ng/ml) compared to baseline (0.06 +/- 0.01 ng/ml) or WMA (0.3 +/- 0.07 ng/ml). Kinin generation again correlated with increases in histamine, PGD2 and TAME-esterase activity and with onset of symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Kininogens in nasal secretions after allergen challenge.

Abstract: Allergic individuals and nonallergic controls were subjected to nasal challenge with allergen; and nasal washes, obtained before and after challenge, were assayed for high molecular weight kininogen (HMWK), total kininogen (TK), albumin and kinins. Following challenge of allergic individuals, HMWK, TK, kinin and albumin all increased dramatically, correlating (p less than 0.001) with the onset of clinical symptoms and with increases in histamine and TAME-esterase activity. No such increases were seen upon challenge of nonallergics. The time course of appearance and disappearance of the kininogens, kinins and albumin were all highly correlated (p less than 0.001 in each case) by linear regression analysis, as were the increases in kinin and each of the proteins during antigen titrations. For each individual, the plasma ratio of HMWK/TK was similar to the ratio of these two proteins in post-challenge nasal washes from the same individual. These findings are consistent with the hypothesis that, during the allergic reaction, vascular permeability increases, allowing a transudation of kininogens from plasma into nasal secretions, where they can provide substrate for kinin-forming enzymes.