Understanding the mechanisms of viral induced asthma: new therapeutic directions

Asthma is a common and debilitating disease that has substantially increased in prevalence in Western Societies in the last 2 decades. Respiratory tract infections by respiratory syncytial virus (RSV) and rhinovirus (RV) are widely implicated as common causes of the induction and exacerbation of asthma. These infections in early life are associated with the induction of wheeze that may progress to the development of asthma. Infections may also promote airway inflammation and enhance T helper type 2 lymphocyte (Th2 cell) responses that result in exacerbations of established asthma. The mechanisms of how RSV and RV induce and exacerbate asthma are currently being elucidated by clinical studies, in vitro work with human cells and animal models of disease. This research has led to many potential therapeutic strategies and, although none are yet part of clinical practise, they show much promise for the prevention and treatment of viral disease and subsequent asthma

TLR2, TLR4 AND MyD88 Mediate Allergic Airway Disease (AAD) and Streptococcus pneumoniae-Induced Suppression of AAD.

BACKGROUND:Exposure to non-pathogenic Streptococcus pneumoniae and vaccination are inversely associated with asthma. Studies in animal models demonstrate that airway administration of S. pneumoniae (live or killed), or its vaccines or components, suppresses the characteristic features of asthma in mouse models of allergic airway disease (AAD). These components could be developed into immunoregulatory therapies. S. pneumoniae components are recognized by Toll-like receptors (TLR) 2 and TLR4, and both induce inflammatory cell responses through the adaptor protein myeloid differentiation primary response gene 88 (MyD88). The involvement of TLR2, TLR4 and MyD88 in the pathogenesis of AAD and asthma is incompletely understood, and has not been studied in S. pneumoniae-mediated suppression of AAD. We investigated the role of TLR2, TLR4 and MyD88 in the development of AAD and S. pneumoniae-mediated suppression of AAD. METHODS AND FINDINGS:OVA-induced AAD and killed S. pneumoniae-mediated suppression of AAD were assessed in wild-type, TLR2-/-, TLR4-/-, TLR2/4-/- and MyD88-/- BALB/c mice. During OVA-induced AAD, TLR2, TLR4 and MyD88 were variously involved in promoting eosinophil accumulation in bronchoalveolar lavage fluid and blood, and T-helper type (Th)2 cytokine release from mediastinal lymph node T cells and splenocytes. However, all were required for the induction of airways hyperresponsiveness (AHR). In S. pneumoniae-mediated suppression of AAD, TLR2, TLR4 and MyD88 were variously involved in the suppression of eosinophilic and splenocyte Th2 responses but all were required for the reduction in AHR. CONCLUSIONS:These results highlight important but complex roles for TLR2, TLR4 and MyD88 in promoting the development of OVA-induced AAD, but conversely in the S. pneumoniae-mediated suppression of AAD, with consistent and major contributions in both the induction and suppression of AHR. Thus, TLR signaling is likely required for both the development of asthma and the suppression of asthma by S. pneumoniae, and potentially other immunoregulatory therapies

LF-15 & T7, Synthetic Peptides Derived from Tumstatin, Attenuate Aspects of Airway Remodelling in a Murine Model of Chronic OVA-Induced Allergic Airway Disease

Background: Tumstatin is a segment of the collagen-IV protein that is markedly reduced in the airways of asthmatics. Tumstatin can play an important role in the development of airway remodelling associated with asthma due to its anti-angiogenic properties. This study assessed the anti-angiogenic properties of smaller peptides derived from tumstatin, which contain the interface tumstatin uses to interact with the aVb3 integrin. Methods: Primary human lung endothelial cells were exposed to the LF-15, T3 and T7 tumstatin-derived peptides and assessed for cell viability and tube formation in vitro. The impact of the anti-angiogenic properties on airways hyperresponsiveness (AHR) was then examined using a murine model of chronic OVA-induced allergic airways disease. Results: The LF-15 and T7 peptides significantly reduced endothelial cell viability and attenuated tube formation in vitro. Mice exposed to OVA+ LF-15 or OVA+T7 also had reduced total lung vascularity and AHR was attenuated compared to mice exposed to OVA alone. T3 peptides reduced cell viability but had no effect on any other parameters. Conclusion: The LF-15 and T7 peptides may be appropriate candidates for use as novel pharmacotherapies due to thei

LF-15 and T7 attenuate OVA-induced changes in lung blood vessel area in a murine model of allergic airways disease.

<p>OVA sensitised mice were exposed to the T3, T7 and LF-15 between Day 25 and Day 115 before mice were sacrificed and the blood vessel area in the lungs was determined by counting CD105 positive blood vessels.*p<0.05 Sham vs OVA, ^$p<0.05 vs OVA, ^$$p<0.01 vs OVA, n = 8.</p

LF-15 attenuates OVA-induced pulmonary inflammation in a murine model of allergic airways disease.

<p>OVA sensitised mice were exposed to the T3, T7 and LF-15 between Day 25 and Day 115 before mice were sacrificed and the extent of pulmonary inflammation was determined by H&E staining. ***p<0.05 Sham vs OVA, ^*p<0.05 LF-15 300 ng vs OVA, n = 8.</p

Probiotic Bifidobacterium longum subsp. longum Protects against Cigarette Smoke-Induced Inflammation in Mice

Bifidobacterium are prominent gut commensals that produce the short-chain fatty acid (SCFA) acetate, and they are often used as probiotics. Connections between the gut and the lung, termed the gut&ndash;lung axis, are regulated by the microbiome. The gut&ndash;lung axis is increasingly implicated in cigarette smoke-induced diseases, and cigarette smoke exposure has been associated with depletion of Bifidobacterium species. In this study, we assessed the impact of acetate-producing Bifidobacterium longum subsp. longum (WT) and a mutant strain with an impaired acetate production capacity (MUT) on cigarette smoke-induced inflammation. The mice were treated with WT or MUT B. longum subsp. longum and exposed to cigarette smoke for 8 weeks before assessments of lung inflammation, lung tissue gene expression and cecal SCFAs were performed. Both strains of B. longum subsp. longum reduced lung inflammation, inflammatory cytokine expression and adhesion factor expression and alleviated cigarette smoke-induced depletion in caecum butyrate. Thus, the probiotic administration of B. longum subsp. longum, irrespective of its acetate-producing capacity, alleviated cigarette smoke-induced inflammation and the depletion of cecal butyrate levels

LF-15 and T7 attenuate OVA-induced airways resistance in a murine model of allergic airways disease.

<p>OVA sensitised mice were exposed to the T3, T7 and LF-15 between Day 25 and Day 115 before specific airway resistance following methacholine challenge was assessed. *p<0.05 OVA+LF-15 vs OVA+ Vehicle control, ^#p<0.05 OVA+Vehicle control vs Sham control, $p<0.05 OVA+T7 vs OVA+ Vehicle control, n = 6.</p

IL-5 and IL-13 release from splenocytes in AAD and KSpn-induced suppression of AAD in MyD88 and TLR deficient mice.

<p>Six-week old BALB/c Wt, MyD88^-/-, TLR2^-/-, TLR4^-/- and TLR2/4^-/- mice were sensitized and challenged with OVA to induce AAD. Some groups were administered KSpn i.t. during sensitization. IL-5 (A) and IL-13 (B) release from splenocytes was determined by ELISA. Data represent mean ± SEM, n = 8. Significance is represented by *<i>P</i> < 0.05, **<i>P</i> < 0.01, ***<i>P</i> < 0.001 (Saline v OVA groups of the same strain), #<i>P</i> < 0.05, ##<i>P</i> < 0.01, ###<i>P</i> < 0.001 (OVA v KSpn+OVA groups of the same strain), †<i>P</i> < 0.05, ††<i>P</i> < 0.01, †††<i>P</i> < 0.001 (Wt v -/- between OVA groups) and ‡<i>P</i> < 0.05, ‡‡‡<i>P</i> < 0.001 (Wt v -/- between KSpn+OVA groups).</p