Effects of IL-13 on airway responses in the guinea pig

Abstract

.-Levels of interleukin (IL)-13 are increased in asthmatic airways. IL-13 has been shown to be necessary and sufficient for allergen-induced airway hyperresponsiveness and increased inflammatory cell counts in bronchoalveolar lavage (BAL) fluid in a murine model of asthma but is thought to protect against airway inflammation when low doses are provided to the guinea pig lung. To determine the role of IL-13 in the guinea pig, we studied the effects of a 360-g/kg dose of nebulized IL-13 in naive animals and of IL-13 abrogation after airway challenge of sensitized animals. Nebulized IL-13 significantly decreased the dose of histamine required to double baseline respiratory system resistance (ED 100, 22 Ϯ 3 vs. 13 Ϯ 2 nmol/kg; P Ͻ 0.05) and was associated with recovery of significantly greater numbers of macrophages, lymphocytes, eosinophils, and neutrophils in BAL fluid. Guinea pigs pretreated with a fusion protein that binds IL-13 [soluble IL-13 receptor ␣2 (sIL-13R␣2)] were protected from developing antigen-induced airway hyperresponsiveness (ED100, 210 Ϯ 50 vs. 20 Ϯ 10 nmol/kg; P Ͻ0.01). sIL-13R␣2 (2 doses of 20 mg/kg) significantly reduced the histological grade of allergen-induced lung eosinophil accumulation, whereas the effects of two doses of 10 mg/kg were not significant. These findings demonstrate that the tissue levels of IL-13 induced by allergen challenge of sensitized animals induce airway hyperresponsiveness and inflammation and that IL-13 is required for the expression of allergen-induced airway hyperresponsiveness in the guinea pig ovalbumin model. interleukin-13; eosinophil; inflammation; airway hyperresponsiveness; ovalbumin IN THE PAST DECADE, ASTHMA has been increasing in prevalence and is now thought to affect 15 million Americans (13). Advances have been made in our understanding of the immunobiology of sensitization (1); the role of interleukin (IL)-4, IL-5, and IL-13 in the development of airway hyperresponsiveness; the recruitment of inflammatory cells to the airway; and the augmented mucus production that follows allergen challenge in a murine system. Strong circumstantial evidence indicates that Th2 lymphocytes and the cytokines they produce are important in the pathogenesis of asthma (3, 5, 6, 10-12, 20, 26).In the mouse, Th2 lymphocytes selectively develop and expand in a process that depends on IL-4 (1, 5). Studies comparing allergen-induced airway hyperresponsiveness in genetically altered receptor-or liganddeficient mice have demonstrated a greater dependence on the IL-4 receptor ␣-chain than on 14). In addition to the IL-4 avid form of the heterodimeric receptor (IL-4 receptor ␣-chain/common ␥-chain), the IL-4 receptor ␣-chain can combine with IL-13 receptor ␣1 and efficiently bind 12,24); this realization in murine biology led to speculation that IL-13 was the mediator responsible for allergen-induced pulmonary inflammatory cell recruitment and airway hyperresponsiveness in the mouse model (2). The availability of the fusion protein soluble sIL-13 receptor ␣2 (sIL-13R␣2), which se...

IL-13 may mediate allergen-induced hyperresponsiveness independently of IL-5 or eotaxin by effects on airway smooth muscle

“…IL-13 gene-deleted mice fail to develop allergen-induced AHR (30), and the inhibition of IL-13 through the administration of a soluble form of the IL-13 receptor (IL-13R␣ 2 ) reverses OVA-induced AHR in mice (31) and guinea pigs (20). In the current study, a neutralizing antibody directed against IL-13 also inhibited the development of AHR after OVA challenge.…”

Gene expression analysis in a murine model of allergic asthma reveals overlapping disease and therapy dependent pathways in the lung

“…8,9 Similarly, we have shown that intratracheal instillation of mIL-13 induced IgE, pulmonary eosinophilia, mucus production and AHR. 8,9,16 In this study, we have extended our analysis of this model using microarray expression profiling and have identified genes uniquely associated with IL-13 activity and antagonism. In addition, we have demonstrated a substantial overlap in gene expression changes following OVA challenge and intratracheal instillation of IL-13.…”

Interleukin-13 inhibits proliferation and enhances contractility of human airway smooth muscle cells without change in contractile phenotype

“…It is actively secreted during the late asthmatic response in mild asthmatic subjects (16) and has been implicated in the development of airway hyperresponsiveness (AHR) in models of allergic asthma. IL-13-genedeleted mice fail to develop allergen-induced AHR (32), and the inhibition of IL-13 through the administration of the soluble IL-13 receptor (IL-13R␣2) reverses ovalbumin-induced AHR in mice (33) and guinea pigs (23). Repeated administration of IL-13 to naïve mice and the overexpression of IL-13 by murine airway epithelium cause AHR (33,38).…”

“…Repeated administration of IL-13 to naïve mice and the overexpression of IL-13 by murine airway epithelium cause AHR (33,38). Although IL-13 promotes inflammation, AHR is rapidly induced by the administration of IL-13 to experimental animals and precedes inflammation (23,31).…”