Inflammation-induced airway smooth muscle responsiveness is strain dependent in mice

Abstract

Different mouse strains display different degrees of inflammation-induced airway hyperresponsiveness in vivo. It is not known whether these variations are attributable to distinct properties of the airway smooth muscle. Therefore, tracheal ring segments from C57BL/6 and BALB/c mice were exposed to three different pro-inflammatory stimuli for 4 days while maintained under tissue-culture conditions: tumour necrosis factor α (100 ng/ml), the Toll-like receptor (TLR) 3 agonist polyI:C (10 µg/ml), and the TLR4 agonist LPS (10 µg/ml). The contractile responses to carbachol, 5-hydroxytryptamine (5-HT) and bradykinin were assessed after culture. In addition, gene expression of TLR1-TLR9, pivotal inflammatory signal transduction proteins (jun-kinase, p38 and p65) and critical negative regulators of inflammation (A20, Itch, Tax1bp1 and RNF11) were studied in tracheal smooth muscle strips, fresh and following treatment for 4 days with LPS, from both strains. No differences between the strains were detected regarding the response of freshly isolated preparations to carbachol, 5-HT and bradykinin. After stimulation with pro-inflammatory mediators, contractions in response to 5-HT and bradykinin, but not to carbachol, were up-regulated. This up-regulation was markedly larger in BALB/c than in C57BL/6 segments and depended on the type of inflammatory stimulus. Expression of the genes investigated did not differ between the two strains. These findings indicate that strain differences in airway hyperresponsiveness can be linked to differences in the responsiveness of airway smooth muscle to pro-inflammatory mediators per se. These differences do not appear to be due to differential expression of TLR or common inflammatory transduction and repressor proteins.

Intranasal Administration of poly(I:C) and LPS in BALB/c Mice Induces Airway Hyperresponsiveness and Inflammation via Different Pathways

“…The low cell count after LPS treatment indicates that the inflammation is a result of MyD88 dependent TLR4 signalling and this differs from TLR3, where inflammation seems to be an effect of MyD88 independent signalling probably through the TRIF pathway. The absence of AHR in the C57BL/6 mice, to at least poly(I:C), is in accordance with the lower increase in smooth muscle reactivity to poly(I:C) in C57BL/6 than BALB/c mice [30], and further argument for that the TLR-induced AHR is mediated through an effect directly on the smooth muscle.…”

“…Even though BALB/c mice are known to be preferred for studies of inflammatory induced AHR, MyD88 deficient mice on BALB/c background are not available. C57BL/6 mice are recognized to exhibit a low degree of inflammation-induced AHR but has similar antigen induced cellular levels in BALF as the BALB/c strain [29], [30]. It was therefore expected that, the repeating of the protocol using the MyD88 deficient C57BL/6 mice, should cause no AHR development, However, poly(I:C) caused a raised cell influx in BALF, something that was not seen after LPS.…”

The Immune Basis of Allergic Lung Disease

“…Disadvantages of the mouse model include distinct anatomical and immunological differences between mice and humans (Safholm et al, 2011). Mouse lungs have fewer airway generations, and most airways lack the smooth muscle bundles found in human airways, which may contribute to differences in bronchoconstriction and AHR.…”

“…Following repeated allergen challenge, tolerance to the allergen and diminished immune responses have been observed in many of these models. Careful titration of allergen exposure is required to induce longterm hyperresponsiveness, airway remodeling, and eosinophilia in the mouse (Safholm et al, 2011).…”

Using the One-Lung Method to Link p38 to Pro-Inflammatory Gene Expression during Overventilation in C57BL/6 and BALB/c Mice

“…Important differences between C57BL/6 and BALB/c relate to airway hyperresponsiveness [10], and responses to bacteria [11]–[13], viruses [14], [15] and parasites [16], [17]. Furthermore, BALB/c mice carry the H-2d locus while C57BL/6 mice carry the H-2b locus similar to differences among humans [18], [19].…”