Neuro-immune interactions in chemical-induced airway hyperreactivity

Abstract

Asthma may be induced by chemical sensitisers, via mechanisms that are still poorly understood. This type of asthma is characterised by airway hyperreactivity (AHR) and little airway inflammation. Since potent chemical sensitisers, such as toluene-2,4-diisocyanate (TDI), are also sensory irritants, it is suggested that chemical-induced asthma relies on neuro-immune mechanisms.We investigated the involvement of transient receptor potential channels (TRP) A1 and V1, major chemosensors in the airways, and mast cells, known for their ability to communicate with sensory nerves, in chemical-induced AHR.In vitro intracellular calcium imaging and patch-clamp recordings in TRPA1- and TRPV1-expressing Chinese hamster ovarian cells showed that TDI activates murine TRPA1, but not TRPV1. Using an in vivo model, in which an airway challenge with TDI induces AHR in TDI-sensitised C57Bl/6 mice, we demonstrated that AHR does not develop, despite successful sensitisation, in Trpa1 and Trpv1 knockout mice, and wild-type mice pretreated with a TRPA1 blocker or a substance P receptor antagonist. TDI-induced AHR was also abolished in mast cell deficient Kit(Wsh) (/Wsh) mice, and in wild-type mice pretreated with the mast cell stabiliser ketotifen, without changes in immunological parameters.These data demonstrate that TRPA1, TRPV1 and mast cells play an indispensable role in the development of TDI-elicited AHR.

IL-13 is a central mediator of chemical-induced airway hyperreactivity in mice

“…Non-specific airway hyperreactivity to methacholine, lung inflammation and immunologic responses are assessed one day later [22]. …”

The emerging role of transient receptor potential channels in chronic lung disease

“…The authors proposed that the AHR following exposure to hypochlorite and ovalbumin depends on a neuroimmune interaction that involves TRPA1-dependent stimulation of sensory neurons and mast cell activation, although the rationale is not obvious given AHR to direct contractile agents is not thought to have a neuronal component as they are thought to activate airway smooth muscle directly [125]. Another article by the same authors demonstrated that TRPA1, TRPV1 and mast cells play an indispensable role in the development of TDI-elicited AHR [126]. In the context of COPD-relevant disease biology, cigarette smoke extract has been shown to evoke IL-8 release from human epithelial cells, smooth muscle cells and fibroblasts and cigarette smoke and acrolein have been shown to release keratinocyte-derived chemokine (murine orthologue) in a murine model.…”

Forced expiration measurements in mouse models of obstructive and restrictive lung diseases

“…FOT measurements have already been used in mouse models of respiratory diseases to investigate pathophysiological changes associated with fibrosis [3], emphysema [4], or asthma [5–8]. Yet, from a pre-clinical perspective, the translational value of the mouse as a model to study respiratory diseases has been challenged and it is not always clear how changes in respiratory mechanics parameters relate to the commonly measured forced expiration (FE) parameters in humans [9].…”