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C G Irvin

Publications and source records attributed to C G Irvin.

At least 55 records · Page 3Linked to original sources
PubMed1995

The detection of collapsible airways contributing to airflow limitation.

The detection of collapsible airways, which may be a component of asthma and emphysema, has important therapeutic implications. We describe a patient with significant airways collapse contributing to his airflow limitation and discuss how collapsible airways can be assessed by the volume difference between what exits the lung as determined by a spirometer and the volume compressed as measured by the plethysmograph. More simply, a large volume difference between the slow and forced vital capacity (SVC-FVC), easily obtained from spirometry, may be used as a surrogate index of airway collapse.

Aged↗
PubMed1995

Bronchial challenge testing.

Airways hyperresponsiveness can occur as solitary evidence of airways dysfunction. Because hyperresponsiveness is associated with the presence and severity of disease, it is important to measure and quantitate airways responsiveness. The most useful challenge procedure appears to be the methacholine challenge, not so much because it offers the best specificity of the challenge procedures but because it has been characterized well. Although the procedures are simple, interpretation of the results is problematic. It is important to remember that the key features of asthma are the periodicity and lability of signs and symptoms. Assessment of airways responsiveness is a significant addition to the armamentarium of the modern diagnosis and treatment of asthma.

Adolescent↗
PubMed1994

Role of cationic proteins in the airway. Hyperresponsiveness due to airway inflammation.

Major basic protein (MBP) is a highly cationic protein found in the granules of eosinophils. It has been postulated that MBP may participate in the pathogenesis of airway hyperresponsiveness exhibited by asthmatic patients. Accordingly, we have employed a rat system to investigate the effect of human MBP instillation on airway responsiveness and the possible role of cationic charge in the determination of this effect. Major basic protein caused a significant increase in airway responsiveness to inhaled methacholine. Two polycations, poly-L-arginine and poly-L-lysine, also increased airway responsiveness to inhaled methacholine. Moreover, two other very different cationic proteins, platelet factor 4 (PF4) and cathepsin G were also capable of inducing airway hyperresponsiveness. These effects were dependent on their positive charge, since the charge--and, hence the effect--of these proteins was neutralized with low molecular weight heparin. In addition, other polyanions, such as low molecular weight heparin, albumin, or dextran sulfate, were also effective. We investigated whether two synthetic cationic proteins, poly-L-arginine and poly-L-lysine, could modify epithelial-dependent responses using a perfused guinea pig tracheal tube preparation. With an intact epithelium, methacholine was some 150 times less potent when applied intraluminally than when applied extraluminally. Perfusion of the luminal surface with cationic proteins increased the potency of intraluminally applied methacholine without modifying the responses to extraluminally applied methacholine. Cationic proteins also attenuated the relaxant effects of intraluminally applied KCl. These effects occurred in the absence of any overt epithelial cell damage. Our data demonstrates that cationic proteins can modify epithelial-dependent responses in the airways.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Cationic protein-induced sensory nerve activation: role of substance P in airway hyperresponsiveness and plasma protein extravasation.

We have previously reported that human eosinophil granule major basic protein and synthetic cationic proteins such as poly-L-arginine and poly-L-lysine, can increase airway responsiveness in vivo. In the present study, we have investigated whether activation of sensory C-fibers is important in this phenomenon. Dose-response curves to methacholine were constructed before and 1 h after intratracheal instillation of poly-L-lysine in anaesthetized spontaneously breathing rats, and the concentration of methacholine required to induce a doubling in total lung resistance was calculated. Poly-L-lysine induced a fivefold increase in airway responsiveness, which was inhibited by neonatal capsaicin treatment and potentiated by phosphoramidon (100 micrograms/ml). Furthermore, pretreatment with either CP, 96-345, or RP-67580 two selective NK-1 receptor antagonists inhibited poly-L-lysine-induced airway hyperresponsiveness and plasma protein extravasation. In vitro, cationic proteins stimulated the release of calcitonin gene-related peptide-like immunoreactivity from perfused slices of the main bronchi. Our results demonstrate that cationic proteins can activate sensory C-fibers in the airways, an effect which is important in the subsequent development of airway hyperresponsiveness and plasma protein extravasation. Cationic proteins may therefore function as a link between inflammatory cell accumulation and sensory nerve activation.

Animals↗
PubMed1993

Cationic proteins alter smooth muscle function by an epithelium-dependent mechanism.

Using a perfused guinea pig tracheal tube preparation, which allows the selective application of agonists to either the serosal or luminal surface, we have investigated whether two synthetic cationic proteins, poly-L-arginine and poly-L-lysine, can modify epithelium-dependent responses. With an intact epithelium, methacholine was approximately 150 times less potent when applied intraluminally than when applied extraluminally. This difference was abolished by chemically removing the epithelium with the detergent CHAPS. Intraluminal application of KCl induced a dose-related relaxation of a precontracted trachea, which was also abolished by epithelium removal. Perfusion of the luminal surface with cationic proteins for 1 h (10 micrograms/ml) increased the potency of intraluminally applied methacholine without modifying the responses to extraluminally applied methacholine. Cationic proteins also attenuated the relaxant effects of intraluminally applied KCl. These effects occurred in the absence of any overt epithelial cell damage. In contrast, when the serosal surface of the trachea was treated with poly-L-arginine, there was no modification of either methacholine-induced contraction or KCl-induced relaxation. The effects of poly-L-arginine were inhibited by coperfusion with the polyanions albumin (10 micrograms/ml) or heparin (100 micrograms/ml). In contrast to cationic proteins, intraluminal perfusion with a polyanion, poly-L-aspartate (10 micrograms/ml), failed to modify either methacholine-induced contraction or KCl-induced relaxation. Our data demonstrate that cationic proteins can modify epithelium-dependent responses in the airways. Although the precise mechanisms are unclear, a role is suggested for a charge-mediated interaction with the respiratory epithelium, resulting in airway smooth muscle dysfunction.

Albumins↗
PubMed1993

Effect of lung volume maintenance during sleep in nocturnal asthma.

Previous studies have shown that lung volume decreases and airway resistance increases during sleep in patients with nocturnal asthma. To determine whether the fall in lung volume per se causes the overnight decrement in forced expiratory volume in 1 s (FEV1) and/or increase in bronchial responsiveness, we investigated the effect of preventing this nocturnal decrease in lung volume. The mean volume change on a baseline night was -16.3 +/- 1.6% from presleep values and on the volume maintenance night +7.1 +/- 3.0% (P = 0.0001). However, this maintenance of lung volume did not alter the overnight decrement in FEV1 (-29.6 +/- 5.2% baseline vs. -30.2 +/- 5.8% volume maintenance). Similarly, the increase in bronchial responsiveness was also unaltered from baseline to volume maintenance nights, with presleep provocative concentrations of methacholine producing a 20% decrement in FEV1 of 0.28 +/- 0.15 vs. 0.22 +/- 0.7 mg/ml, respectively, and postsleep values of 0.07 +/- 0.03 vs. 0.04 +/- 0.02 mg/ml, respectively. Thus the fall in lung volume during sleep in the nocturnal asthmatic patient is a result, not a cause, of the overnight worsening of lung function.

Adult↗
PubMed1993

Increased lower airways responsiveness associated with sinusitis in a rabbit model.

The association between sinusitis and asthma has been clinically recognized, but its precise nature is controversial. We studied the relationship between sinusitis and lower airways function in a rabbit model of sterile maxillary sinusitis induced by the chemotactic complement fragment C5a des arg. Animals kept in a head-up position following experimental sinusitis demonstrated a significant increase in airways responsiveness (AWR) to histamine. In contrast, animals of which the sinuses were injected with a saline diluent and in which no sinus inflammation developed had no increase in AWR. Experiments were subsequently carried out to investigate some of the potential mechanisms for these observations. A group of rabbits in which a distal site of inflammation was induced did not demonstrate increased AWR. Likewise, when sinus inflammation was established but passage of fluid to the lower airways was prevented, either by intubation or by head-down positioning, there was no change in AWR. A fourth experiment was designed to decrease complement factor activity before placing the animals in a head-up position. This led to the same degree of increased AWR. Neither the histology nor the bronchoalveolar lavage data demonstrated significant lower airways inflammation in any group. We conclude that sterile sinusitis can increase lower airways responsiveness to histamine in a rabbit model. The most likely mechanism for this effect is the postnasal dripping of cells or cell products into the lower airway. The role of a nasobronchial reflex or inflammatory mediator absorption could not be demonstrated in this model.

Animals↗
PubMed1993

Cationic proteins induce airway hyperresponsiveness dependent on charge interactions.

It has previously been demonstrated that human eosinophil-derived granule major basic protein (MBP) can increase airway responsiveness after intratracheal administration in the rat. This effect was mimicked by synthetic polycations, suggesting that charge interactions may be important in the development of airway hyperresponsiveness (AHR). To support this hypothesis, we investigated whether two other cationic proteins, platelet factor 4 (PF4) and cathepsin G, were capable of inducing AHR. Furthermore, to determine whether these effects were dependent on their positive charge, the charge of these proteins was neutralized with low molecular weight heparin. In addition, we have examined whether the effect of a synthetic polycation, poly-L-lysine could be inhibited by low molecular weight heparin, albumin, or dextran sulphate. MBP, PF4, or cathepsin G induced a 2- to 3-fold increase in airway responsiveness 1 h after instillation, as assessed by the dose of inhaled methacholine required to increase total lung resistance by 100%. Admixing these native cationic proteins with low molecular weight heparin inhibited the development of AHR. Similarly, poly-L-lysine increased airway responsiveness that was inhibited not only by low molecular weight heparin but also by two other anionically charged molecules, albumin and dextran sulphate. These findings suggest that charge interactions in the airways are important not only in alterations in airway responsiveness induced by eosinophil-derived MBP, but also because they underlie altered airway responsiveness after treatment with other cationic proteins. The precise mechanisms involved in this phenomenon remain to be determined.

Albumins↗
PubMed1993

The effect of human eosinophil granule major basic protein on airway responsiveness in the rat in vivo. A comparison with polycations.

Major basic protein (MBP) is a highly cationic protein found in the granules of eosinophils. It has been postulated that MBP may participate in the pathogenesis of airway hyperresponsiveness exhibited by asthmatic patients. Accordingly, we used a rat model to investigate the effect of human MBP instillation on airway responsiveness and the possible role of cationic charge in the determination of this effect. Dose-response characteristics to inhaled methacholine (MDRC) were determined at baseline, and the animals were allowed to recover. Then animals in the experimental group received 100 micrograms of purified human MBP via direct instillation into the trachea. One hour after instillation, the MDRC were again assessed. Control animals received (in lieu of MBP) buffer from the void volume pool of the same chromatography column used to purify the MBP. One hour after instillation of MBP there was a significant increase in airway responsiveness to inhaled methacholine, whereas control animals exhibited no increase in airway responsiveness. Some animals from the MBP group were restudied 48 h after MBP instillation, by which time airway responsiveness had returned to baseline level. The effect of the polycations poly-L-arginine and poly-L-lysine on airway responsiveness was also examined. As with MBP, airway responsiveness to inhaled methacholine increased 1 h after the instillation of either polycation. In addition, acetylation of the charged groups on poly-L-lysine resulted in a loss of this effect. Histologic examination of the airways failed to reveal airway epithelial shedding 1 h after MBP or polycation instillation.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗
PubMed1993

Anatomic correlates of reversible restrictive lung disease.

A 19-year-old woman presented with lifelong asthma. Pulmonary function studies revealed a mixed restrictive-obstructive pattern, with significantly decreased elastic recoil as demonstrated by a pressure-volume study. Upon administration of inhaled bronchodilator, however, the patient's lung volume and compliance returned to normal, illustrating the rare phenomenon of reversible restrictive lung disease. Open lung biopsy revealed respiratory bronchiolitis, confirming the suspected involvement of small airways. Mechanisms of reversible restriction, specifically alveolar duct constriction, are discussed. The authors speculate on the observed relation between anatomic and physiologic abnormalities.

Adrenal Cortex Hormones↗
PubMed1992

Respiratory mechanics of the coatimundi and woodchuck.

The coatimundi breathes with a large tidal volume and relatively short TE/TTOT while the woodchuck has a relatively long TE/TTOT compared to other mammals. Hence, the respiratory mechanics of the coatimundi and woodchuck were studied to determine whether mechanics play any role in the differences in breathing pattern observed in these two mammals of similar body size. Although static respiratory system compliance was less and lower airway resistance was greater in the woodchuck compared to the coati there was no significant difference in deflationary time constant that could contribute to the difference in expiratory time. Both species exhibit less compliant chest walls than would be predicted for animals this size (4.5 and 5 kg) and the coati lung compliance is greater than that of the woodchuck or the prediction. The large tidal volume in the coati may be attributed in part to the large lung volume of this species (2.2 times the allometric prediction). The differences in breathing pattern are more likely related to differences in the control of breathing (i.e. regulation of expiratory airflow and inspiratory onset) than to differences in respiratory mechanics.

Animals↗
PubMed1992

Nasal beclomethasone prevents the seasonal increase in bronchial responsiveness in patients with allergic rhinitis and asthma.

Experimental studies have demonstrated that induction of a nasal allergic reaction can lead to an increase in bronchial responsiveness (BR). To assess the clinical relevance of these experimental changes to chronic asthma, we sought to determine the effect of nasal beclomethasone dipropionate (Bdp) on BR in patients with seasonal allergic rhinitis and asthma. Eighteen subjects with histories of seasonal allergic rhinitis and asthma during the fall pollen season with positive skin tests to short ragweed and bronchial hyperresponsiveness to inhaled methacholine were assigned to receive either nasal Bdp (336 micrograms/day) or placebo for the entire ragweed season. Patients recorded daily nasal and chest symptoms, nasal blockage index, oral peak expiratory flow rates, and supplemental medication use. BR to methacholine was measured during the baseline period and 6 weeks into the ragweed season. Although the Bdp group did have a significant improvement in nasal blockage index, there was no improvement in daily asthma symptom scores, oral peak expiratory flow, or asthma medication use. However, subjects treated with Bdp were protected from the increase in BR seen in the placebo group (geometric mean PC20 placebo group: baseline = 0.70, week 6 = 0.29; Bdp group: baseline = 0.80, week 6 = 0.93; intergroup difference, p = 0.022). We conclude that nasal corticosteroid therapy can prevent the increase in BR associated with seasonal pollen exposure in patients with allergic rhinitis and asthma.

Administration, Intranasal↗
PubMed1992

Sinusitis and asthma: an animal model.

We have developed an animal model in which nonspecific lower airways hyperresponsiveness to inhaled histamine was elicited in rabbits after complement-induced maxillary sinusitis. The most likely mechanism to explain this occurrence is the direct passage ("postnasal drip") of inflammatory mediators from the upper to the lower respiratory tract. The contribution of other potential mechanisms, such as the blood-borne delivery of inflammatory mediators, nasobronchial reflexes, and passage of cells with the induction of a secondary inflammatory process, could not be demonstrated. Rather, the most likely explanation for the current finding is the passage of mediators elaborated from activated inflammatory cells into the lower airways. Whether these findings explain the common clinical association of upper airways disease to lower airways dysfunction in sinusitis and asthma remains to be determined. These results suggest that even small numbers of granulocytes, when activated, can exert significant effect on lower airways function. It is perhaps appropriate to speculate at this point about the anecdotal but dramatic improvement in the asthma of patients with sinusitis who undergo surgery. The current results cause us to suggest that this success is due to the removal of the source of inflammatory products that drip into the lung. More important, these current results may have an important implication in the diagnosis of asthma. Finally, there is the clear conclusion that airways dysfunction can be caused by a mechanism that is associated with inflammation but without evidence of cell migration into the airways.

Animals↗
PubMed1992

Aerosolized antigen exposure without adjuvant causes increased IgE production and increased airway responsiveness in the mouse.

Inhalation of an antigen, ovalbumin (OVA), in the absence of adjuvant has been demonstrated to induce an immune response that is associated with increased airway responsiveness. Determination of OVA-specific serum IgE and IgG antibody responses revealed an early increase in antibody titers that were initially restricted to the IgE class. Subsequently, IgG antibody titers increased and IgE antibody plateaued. Furthermore, we observed a tenfold increase in the number of lymphocytes caused by a predominant expansion of CD3+ T cells in the peribronchial-associated lymph modes (PBLNs) of sensitized animals compared with the numbers of cells in control animals or in the gut-associated lymphoid tissue. The sensitized animals demonstrated an increase in airway responsiveness to intravenous methacholine challenge. Analysis of in vitro immunoglobulin production by spleen mononuclear cells revealed increased spontaneous IgE production that was more than fourfold enhanced in the presence of OVA, but IgG production was not increased. Spleen and PBLN lymphocytes, but not lymphocytes from gut-draining lymph nodes, demonstrated a proliferative response to OVA. Control animals exhibited no proliferative response to OVA. Histopathologic examination of the sensitized lung revealed an absence of acute inflammatory cells (e.g., neutrophils and macrophages), lymphocytes, or monocytes at the time of the increased airway hyperresponsiveness. These data indicate that, after sensitization of mice by inhalation of antigen, the animals develop a specific IgE antibody response, expansion of PBLN lymphocyte numbers, and increased airway hyperresponsiveness in the absence of signs of airway inflammation.

Adjuvants, Immunologic↗
PubMed1992

Changes in bronchial responsiveness following nasal provocation with allergen.

The relationship between upper airway inflammation and asthma is controversial. In the current study, we sought to investigate the relationship between allergic rhinitis and lower airway dysfunction by performing double-blind, randomized nasal challenges with allergen or placebo. Subjects were selected for a prior history of asthma exacerbations after the onset of seasonal allergic rhinitis symptoms. After the induction of a marked nasal-allergic reaction (with a technique of nasal provocation that limited allergen delivery to the nose), there were no changes in FEV1, specific conductance, or lung volumes either 30 minutes or 4 1/2 hours after nasal allergen challenge, nor any changes in peak flow rates followed hourly until the next day. However, nasal provocation with allergen resulted in a relative increase in bronchial responsiveness to methacholine compared with that to placebo (p = 0.011 at 30 minutes and p = 0.0009 at 4 1/2 hours after challenge). Our study suggests that, although a nasal-allergic response does not induce airflow limitation of the lower airways, it can alter bronchial responsiveness.

Adolescent↗
PubMed1992

Effects of hyperbaric oxygen and a perfluorooctylbromide emulsion on the radiation responses of tumors and normal tissues in rodents.

Perfluorochemical emulsions are being examined in many laboratory and clinical studies as possible adjuncts to radiotherapy and chemotherapy. The studies reported here examine the clinical potential of hyperbaric oxygen (HBO) in combination with a highly concentrated perfluorochemical emulsion (Oxygent) containing 100% w/v perfluorooctylbromide (PFOB). HBO alone produced only a small improvement in the radiation response of BA1112 tumors in WAG/rij rats, while regimens combining HBO with Oxygent produced much greater radiation sensitization. A sham emulsion, formulated without the O2-carrying PFOB, did not alter the radiation response of the tumors in comparison with that seen with HBO alone. Neither HBO nor Oxygent plus HBO altered the radiosensitivity of bone marrow progenitor cells in BALB/c mice. HBO alone augmented skin reactions in BALB/c mice, but addition of Oxygent did not alter the skin reactions in comparison to those seen with HBO alone. Regimens combining Oxygent with HBO selectively increased the radiation sensitivity of tumors relative to normal tissues, thereby enhancing the therapeutic ratio. These results support the potential usefulness of perfluorochemical emulsions and HBO in clinical radiation therapy.

Animals↗