Abstract
It is well-established that bacterial and viral infections have an exacerbating effect on allergic asthma, particularly aggravating respiratory symptoms, such as airway hyperresponsiveness (AHR). The mechanism by which these infections alter AHR is unclear, but some studies suggest that Toll-like receptors (TLRs) play a role. In this study, we investigated the impact of TLR3 and TLR4 ligands on AHR and airway inflammation in a model of pre-established allergic inflammation. Female BALB/c mice were sensitised and challenged intranasally (i.n.) with either PBS or ovalbumin (OVA) and subsequently i.n. challenged with poly (I:C) (TLR3) or LPS (TLR4) for four consecutive days. The response to methacholine was measured in vivo; cellular and inflammatory mediators were measured in blood, lung tissue and broncheoalveolar lavage fluid (BALF). OVA challenge resulted in an increase in AHR to methacholine, as well as increased airway eosinophilia and TH2 cytokine production. Subsequent challenge with TLR agonists resulted in a significant increase in AHR, but decreased TLR-specific cellular inflammation and production of immune mediators. Particularly evident was a decline in LPS-induced neutrophilia and neutrophil-associated cytokines following LPS and poly (I:C) treatment. The present data indicates that TLRs may play a pivotal role in AHR in response to microbial infection in allergic lung inflammation. These data also demonstrate that aggravated AHR occurs in the absence of an exacerbation in airway inflammation and that allergic inflammation impedes a subsequent inflammatory response to TLRs. These results may parallel clinical signs of microbial asthma exacerbation, including an extended duration of illness and increased respiratory symptoms.
Highlights
It is a well-established clinical phenomenon that viral and bacterial infections are primary risk factors for acute asthma exacerbations [1,2]
Airway Hyperresponsiveness To investigate the impact of TLR3 and TLR4 stimulation on airway function in animals with pre-established allergic inflammation, a dose-response to MCh was carried out in challenged animals with and without prior lung inflammation
Cellular Inflammation To investigate the impact of pre-established allergic inflammation on the inflammatory response to LPS and poly (I:C), cellular inflammation was analysed in blood, lung tissue and broncheoalveolar lavage fluid (BALF) (Figure 2)
Summary
It is a well-established clinical phenomenon that viral and bacterial infections are primary risk factors for acute asthma exacerbations [1,2] Viral infections, such as respiratory syncytial virus (RSV) and human rhinovirus (HRV), are the most predominant forms of asthma exacerbation, believed to cause almost 50% of exacerbations in adults [3]. Bacterial infections, such as Streptococcus pneumoniae, Haemophilius influenzae and Moraxella cattarhalis are present during asthma exacerbations and have been shown to be both triggers of the exacerbation or play an opportunistic role following viral infection [4]. Recent data suggest that pattern recognition receptors (PRRs) of the innate immune system may play a pivotal role [8,9,10]
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