Isbufylline, a new xanthine derivative, inhibits airway hyperresponsiveness and airway inflammation in guinea pigs

Recently, we have shown that allergen-induced airway hyperresponsiveness (AHR) after the early (EAR) and late (LAR) asthmatic reaction in guinea pigs could be reversed acutely by inhalation of the Rho kinase inhibitor Y-27632. The present study addresses the effects of pretreatment with inhaled Y-27632 on the severity of the allergen-induced EAR and LAR, the development of AHR after these reactions, and airway inflammation. Using permanently instrumented and unrestrained ovalbumin (OA)-sensitized guinea pigs, single OA challenge-induced EAR and LAR, expressed as area under the lung function (pleural pressure, Ppl) time-response curve, were measured, and histamine PC100 (provocation concentration causing a 100% increase of Ppl) values were assessed 24 h before, and at 6 and 24 h after, the OA challenge (after the EAR and LAR, respectively). Thirty minutes before and 8 h after OA challenge, saline or Y-27632 (5 mM) was nebulized. After the last PC100 value, bronchoalveolar lavage (BAL) was performed, and the inflammatory cell profile was determined. It was demonstrated that inhalation of Y-27632 before allergen challenge markedly reduced the immediate allergen-induced peak rise in Ppl, without significantly reducing the overall EAR and LAR. Also, pretreatment with Y-27632 considerably protected against the development of AHR after the EAR and fully prevented AHR after the LAR. These effects could not be explained by a direct effect of Y-27632 on the histamine responsiveness, because of the short duration of the acute bronchoprotection of Y-27632 (<90 min). In addition, Y-27632 reduced the number of total inflammatory cells, eosinophils, macrophages, and neutrophils recovered from the BAL. Altogether, inhaled Y-27632 protects against acute allergen-induced bronchoconstriction, development of AHR after the EAR and LAR, and airway inflammation in an established guinea pig model of allergic asthma.

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Role of tachykinin NK1 and NK2 receptors in allergen-induced early and late asthmatic reactions, airway hyperresponsiveness, and airway inflammation in conscious, unrestrained guinea pigs

Clinical & Experimental Allergy ◽

10.1046/j.1365-2222.1999.00008.x ◽

1999 ◽

Vol 29 ◽

pp. 48-52 ◽

Cited By ~ 6

Author(s):

M. Schuiling ◽

A. B. Zuidhof ◽

J. Zaagsma ◽

H. Meurs

Keyword(s):

Airway Inflammation ◽

Guinea Pigs ◽

Airway Hyperresponsiveness

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L -Selectin is required for the development of airway hyperresponsiveness but not airway inflammation in a murine model of asthma

Journal of Allergy and Clinical Immunology ◽

10.1067/mai.2001.114703 ◽

2001 ◽

Vol 107 (6) ◽

pp. 1019-1024 ◽

Cited By ~ 41

Author(s):

Lynne C. Fiscus ◽

Jenny Van Herpen ◽

Douglas A. Steeber ◽

Thomas F. Tedder ◽

Mimi L.K. Tang

Keyword(s):

Airway Inflammation ◽

Murine Model ◽

Airway Hyperresponsiveness

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HYB 2055 ? a second-generation immunomodulatory oligonucleotide containing CpR motifs potently reverses allergic airway inflammation and airway hyperresponsiveness in mouse models of established asthma*1

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2004.01.240 ◽

2004 ◽

Vol 113 (2) ◽

pp. S219

Author(s):

E KANDIMALLA

Keyword(s):

Airway Inflammation ◽

Mouse Models ◽

Airway Hyperresponsiveness ◽

Second Generation ◽

Allergic Airway Inflammation

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Contrasting roles for the receptor for advanced glycation end-products on structural cells in allergic airway inflammation vs. airway hyperresponsiveness

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00087.2015 ◽

2015 ◽

Vol 309 (8) ◽

pp. L789-L800 ◽

Cited By ~ 13

Author(s):

Akihiko Taniguchi ◽

Nobuaki Miyahara ◽

Koichi Waseda ◽

Etsuko Kurimoto ◽

Utako Fujii ◽

...

Keyword(s):

Airway Inflammation ◽

Airway Hyperresponsiveness ◽

Allergic Airway Inflammation ◽

T Helper ◽

Advanced Glycation ◽

Glycation End Products ◽

End Products ◽

Group 2 ◽

Airway Responses

The receptor for advanced glycation end-products (RAGE) is a multiligand receptor that belongs to the immunoglobulin superfamily. RAGE is reported to be involved in various inflammatory disorders; however, studies that address the role of RAGE in allergic airway disease are inconclusive. RAGE-sufficient (RAGE+/+) and RAGE-deficient (RAGE−/−) mice were sensitized to ovalbumin, and airway responses were monitored after ovalbumin challenge. RAGE−/− mice showed reduced eosinophilic inflammation and goblet cell metaplasia, lower T helper type 2 (Th2) cytokine production from spleen and peribronchial lymph node mononuclear cells, and lower numbers of group 2 innate lymphoid cells in the lung compared with RAGE+/+ mice following sensitization and challenge. Experiments using irradiated, chimeric mice showed that the mice expressing RAGE on radio-resistant structural cells but not hematopoietic cells developed allergic airway inflammation; however, the mice expressing RAGE on hematopoietic cells but not structural cells showed reduced airway inflammation. In contrast, absence of RAGE expression on structural cells enhanced innate airway hyperresponsiveness (AHR). In the absence of RAGE, increased interleukin (IL)-33 levels in the lung were detected, and blockade of IL-33 receptor ST2 suppressed innate AHR in RAGE−/− mice. These data identify the importance of RAGE expressed on lung structural cells in the development of allergic airway inflammation, T helper type 2 cell activation, and group 2 innate lymphoid cell accumulation in the airways. RAGE on lung structural cells also regulated innate AHR, likely through the IL-33-ST2 pathway. Thus manipulating RAGE represents a novel therapeutic target in controlling allergic airway responses.

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