Chemical and Antigen Challenge

To examine the contribution of bone marrow–derived factors to differences in the allergen-induced eosinophilic airway inflammation observed in subjects with asthma with an isolated immediate airway response (early responders) versus those with both an early and late response (dual responders), Dorman and colleagues examined blood, bone marrow aspirates, and sputum in 26 subjects with mild, stable asthma. In dual responders, allergen inhalation was associated with a rapid onset of IL-3–dependent eosinophilopoiesis in the bone marrow, detectable as early as 5 hours, and sustained IL-5–dependent eosinophilopoiesis at 12 and 24 hours. IL-5 protein levels increased in serum and bone marrow at 12 and 24 hours in dual responders only. There was significant correlation between IL-5–responsive eosinophil/basophil colony-forming units and IL-5 protein levels in the bone marrow, suggesting that both airway and blood eosinophilia in dual responders are sustained by an IL-5–responsive, eosinophil-differentiating process in the bone marrow. At 48 hours after allergen, bone marrow IL-5 and eosinophilopoiesis decreased, in association with increased IFN- ${gamma}$ . Because these changes occurred only in dual responders who developed peripheral blood and airway eosinophilia and prolonged airway hyperresponsiveness, the authors concluded that bone marrow eosinophilopoiesis and airway eosinophilia play a role in allergen-induced airway hyperresponsiveness.

The fate of eosinophil progenitor cells in the bone marrow after allergen challenge is not well characterized. Dorman and colleagues used flow cytometry to measure CD34⁺ and CD34⁺IL-5R ${alpha}$ ⁺ cells in induced sputum from subjects with asthma and normal control subjects before and 7 and 24 hours after allergen inhalation. At baseline, the proportion of airway CD34⁺ cells was greater in subjects with asthma than in normal control subjects. After allergen challenge, CD34⁺ cells in sputum increased at 7 hours in all subjects with asthma, and remained elevated only in dual responders. The proportion of CD34⁺ cells expressing IL-5R ${alpha}$ increased in dual responders only; this change occurred in conjunction with increases in IL-5 protein. The authors suggested that CD34⁺ progenitor cells migrate from the bone marrow to the airways, where, in the presence of IL-5, they differentiate into eosinophils.

Erpenbeck and colleagues tested the hypothesis that administration of a natural porcine surfactant given before segmental allergen challenge of subjects with asthma would reduce the subsequent airway inflammatory reaction. This hypothesis stems, at least in part, from the observation that surfactant deficiency occurs in at least some patients with asthma. Surprisingly, they observed that surfactant treatment augmented eosinophilic inflammation, plus eotaxin and IL-5 levels, 24 hours after allergen challenge. This increase in Th2-related inflammatory factors was associated with decreased levels of IFN- ${gamma}$ and IFN- ${gamma}$ staining T cells. The mechanism or mechanisms by which this occurs and whether other surfactants would also have this proinflammatory effect remain to be determined.

Liu and collaborators reported the generation of both Th1 and Th2 chemokines in human patients with asthma challenged segmentally with antigen. There was a correlation between numbers of airway (bronchoalveolar lavage) eosinophils and the Th2 cytokines IL-5 and IL-13, whereas the concentration of airway lymphocytes correlated with both Th2 and Th1 chemokines (monokine-induced by IFN- ${gamma}$ , IFN- ${gamma}$ –inducible protein-10). Furthermore, concentrations of both types of chemokines were higher in those subjects with asthma who displayed a late, as well as early, airway reaction after whole lung allergen inhalation, in comparison with subjects with asthma who only displayed an early airway response after allergen. These results suggest that activation of both Th1 and Th2 pathways are greater in these dual-responding patients with asthma.

In 19 patients with intermittent asthma related to sensitivity to cats, Lieutier-Colas and coworkers determined whether the response to bronchial challenge with cat allergen (Fel d 1) is influenced by the size of the nebulized particles. Three nebulizers were used to deliver aerosols with mass median aerodynamic diameters of 1.4, 4.8, and 10.3 痠. The provocative dose of Fel d 1 inducing a 20% decrease in FEV₁ (PD₂₀) was 271 ng for a particle diameter of 1.4 痠, 46 ng for a particle diameter of 4.8 痠, and 13.5 ng for a particle diameter of 10.3 痠. The authors conclude that patients with asthma and cat sensitivity develop a bronchial response with much smaller amounts of cat allergen when it is inhaled with large particles as opposed to smaller particles.

In 36 patients with mild-to-moderate asthma and allergy to house dust, de Kluijver and coworkers did a three-arm double-blind trial. Patients inhaled a low dose of house dust mite allergen over 10 working days (Days 1 to 5 and Days 8 to 12), and were then randomized to experimental infection with rhinovirus or placebo (Days 15 and 16). Exposure to allergen produced decreases in FEV₁ and the provocative dose of histamine causing a decrease in FEV₁, and increases in exhaled nitric oxide and sputum eosinophils. Infection with rhinovirus 16 produced a decrease in FEV₁, and increases in sputum interleukin-8, sputum neutrophils, and neutrophil elastase. Successive allergen exposure and rhinovirus infection did not have any synergistic or additive effect on any clinical or inflammatory outcome. The authors conclude that inhalation of a low dose of allergen and experimental infection with rhinovirus 16 induces distinct inflammatory profiles, and that a preceding allergen exposure does not influence the severity of rhinovirus-induced exacerbations of asthma. An editorial commentary by Johnston accompanies this article.

Some researchers think that thickening of the airway wall causes airway hyperresponsiveness and others think it protects against airway narrowing. In 45 patients with stable asthma (23 of whom were receiving inhaled glucocorticoids), Niimi and coworkers obtained helical computed tomography and a methacholine dose嫾esponse curve; sputum was also induced in a subgroup of 30 patients (16 of whom were receiving inhaled glucocorticoids). Airway sensitivity on methacholine testing was positively correlated with the eosinophil count (induced sputum), both in patients receiving glucocorticoids (r = 0.57) and in patients not receiving glucocorticoids (r = 0.49), but not with airway wall thickness. Airway reactivity on methacholine testing was negatively correlated with airway wall thickness, both in patients receiving glucocorticoids (r = -0.56) and in patients not receiving glucocorticoids (r = -0.55), but not with sputum eosinophil count. The authors conclude that thickening of the airway wall attenuates airway reactivity in patients with asthma. An editorial commentary by Pare accompanies this article.

Citations 1-8 of 8 total displayed.

Enhanced Generation of Helper T Type 1 and 2 Chemokines in Allergen-induced Asthma

Linying Liu, Nizar N. Jarjour, William W. Busse, and Elizabeth A. B. Kelly
Am. J. Respir. Crit. Care Med. 169: 1118 -1124. First published online as doi:10.1164/rccm.200312-1659OC [Abstract] [Full text]

Kinetics of Bone Marrow Eosinophilopoiesis and Associated Cytokines after Allergen Inhalation

Sandra C. Dorman, Roma Sehmi, Gail M. Gauvreau, Rick M. Watson, Ronan Foley, Graham L. Jones, Judah A. Denburg, Mark D. Inman, and Paul M. O'Byrne
Am. J. Respir. Crit. Care Med. 169: 565 -572. First published online as doi:10.1164/rccm.200307-1024OC [Abstract] [Full text]

Natural Porcine Surfactant Augments Airway Inflammation after Allergen Challenge in Patients with Asthma

Veit J. Erpenbeck, Andreas Hagenberg, Yasmin Dulkys, Jörn Elsner, Ralf Bälder, Harald Krentel, Marc Discher, Armin Braun, Norbert Krug, and Jens M. Hohlfeld
Am. J. Respir. Crit. Care Med. 169: 578 -586. First published online as doi:10.1164/rccm.200301-104OC [Abstract] [Full text]

Experimental Models of Rhinovirus-induced Exacerbations of Asthma: Where to Now?

Sebastian L. Johnston
Am. J. Respir. Crit. Care Med. 168: 1145-1146. [Full text]

Are Rhinovirus-induced Airway Responses in Asthma Aggravated by Chronic Allergen Exposure?

Josephine de Kluijver, Christine E. Evertse, Jacob K. Sont, Jasmijn A. Schrumpf, Christel J. G. van Zeijl-van der Ham, Claire R. Dick, Klaus F. Rabe, Pieter S. Hiemstra, and Peter J. Sterk
Am. J. Respir. Crit. Care Med. 168: 1174 -1180. First published online as doi:10.1164/rccm.200212-1520OC [Abstract] [Full text]

Airway Hyperresponsiveness in Asthma: Geometry Is Not Everything!

Peter D. Paré
Am. J. Respir. Crit. Care Med. 168: 913-914. [Full text]

Relationship of Airway Wall Thickness to Airway Sensitivity and Airway Reactivity in Asthma

Akio Niimi, Hisako Matsumoto, Masaya Takemura, Tetsuya Ueda, Kazuo Chin, and Michiaki Mishima
Am. J. Respir. Crit. Care Med. 168: 983 -988. First published online as doi:10.1164/rccm.200211-1268OC [Abstract] [Full text]

Bronchial Challenge Tests in Patients with Asthma Sensitized to Cats: The Importance of Large Particles in the Immediate Response

Florence Lieutier-Colas, Ashok Purohit, Pierre Meyer, Jean-François Fabries, Marie-Christine Kopferschmitt, Jean-François Dessanges, Gabrielle Pauli, and Frédéric de Blay
Am. J. Respir. Crit. Care Med. 167: 1077-1082. [Abstract] [Full text]

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