Airway Exposure Levels of Lipopolysaccharide Determine Type 1 versus Type 2 Experimental Asthma

Abstract

Allergic asthma is characterized by airway inflammation initiated by adaptive immune responses to aeroallergens. Recent data suggest that severe asthma may be a different form of asthma rather than an increase in asthma symptoms and that innate immune responses to LPS can modulate adaptive immune responses to allergens. In this study, we evaluated the hypothesis that airway exposure to different doses of LPS induces different form of asthma. Our study showed that neutrophilic inflammation and IFN-γ expression were higher in induced sputum from severe asthma patients than from mild to moderate asthmatics. Animal experiments indicated that allergen sensitization with low-dose LPS (0.1 μg) induced type 2 asthma phenotypes, i.e., airway hyperresponsiveness, eosinophilic inflammation, and allergen-specific IgE up-regulation. In contrast, allergen sensitization with high-dose LPS (10 μg) induced asthma phenotypes, i.e., airway hyperresponsiveness and noneosinophilic inflammation that were not developed in IFN-γ-deficient mice, but unaffected in the absence of IL-4. During the allergen sensitization period, TNF-α expression was found to be enhanced by both low- and high-dose LPS, whereas IL-12 expression was only enhanced by high-dose LPS. Interestingly, the asthma phenotypes induced by low-dose LPS, but not by high-dose LPS, were completely inhibited in TNF-α receptor-deficient mice, whereas the asthma phenotypes induced by high-dose LPS were abolished in the homozygous null mutation of the STAT4 gene. These findings suggest that airway exposure levels of LPS induces different forms of asthma that are type 1 and type 2 asthma phenotypes by high and low LPS levels, respectively.

Aspirin attenuates the anti-inflammatory effects of theophylline via inhibition of cAMP production in mice with non-eosinophilic asthma

“…It reduces the recruitment of activated T-cells into the lungs of asthmatic individuals and decreases the number of activated T-cells in BAL fluids collected after allergen challenge (Kidney et al, 1995;Jaffar et al, 1996). Our previous data indicate that neutrophilic lung inflammation due to lipopolysaccharide-containing allergen sensitization occurs primarily through the Th1 immune response (Kim et al, 2007). Our present in vivo data show that theophylline inhibits the recruitment of Th1 cells into the lung after allergen challenge, thus reducing neutrophilic inflammation.…”

“…In patients with nocturnal asthma, theophylline inhibits the influx of neutrophils and, to a lesser extent, eosinophils (Kraft et al, 1996). It also inhibits neutrophilic inflammation in patients with severe asthma (Wenzel et al, 1997;Jatakanon, et al, 1999;Kim et al, 2007), and COPD (Culpitt et al, 2002). In vitro, theophylline has inhibitory effects on inflammatory mediators released from neutrophils and on neutrophil chemotaxis (Nielson et al, 1988;Yasui et al, 2000).…”

“…Recently, we reported non-eosinophilic asthma phenotypes induced by airway sensitization with lipopolysaccharide-containing allergens, which are induced by allergen-specific type 1 T helper cell (Th1) response (Kim et al, 2007). We first evaluated the therapeutic effects of theophylline treatment on the development of lung inflammation in the lipopolysaccharide asthma model.…”

“…The role of IFN-γ on the adverse effect of ASA on the anti-inflammatory effects of theophylline Because sensitization with lipopolysaccharide-con- taminated allergens induces lung inflammation mainly via the Th1 immune response (Kim et al, 2007), we evaluated the role of IFN-γ in ASA-exacerbated inflammation using IFN-γ KO and WT (both C57BL/6 background) mice. Theophylline + ASA co-treatment significantly reduced BAL cellularity in ovalbumin/lipopolysaccharide-sensitized IFN-γ KO mice compared to WT mice sensitized in the same manner ( Figure 2C).…”

Modulação da resposta alérgica por BCG recombinante em modelo murino de asma.

“…É importante ressaltar que, embora tenhamos demonstrado que as cepas micobacterianas geraram uma maior produção de IFN-γ no tecido pulmonar dos animais submetidos ao protocolo profilático, não detectamos nenhuma evidência de que estas estariam gerando uma inflamação pulmonar mediada por células Th1, pois os grupos de animais tratados com BCG ou rBCG-S1PT, não apresentaram broncorreatividade exacerbada à metacolina ou inflamação neutrofílica pulmonar, fenótipos característicos da asma tipo 1 (95) .…”