Abstract
Airway vagal hypertonia is closely related to the severity of asthma; however, the mechanisms of its genesis are unclear. This study aims to prove that asthmatic airway vagal hypertonia involves neuronal Cl– dyshomeostasis. The experimental airway allergy model was prepared with ovalbumin in male adult Sprague-Dawley rats. Plethysmography was used to evaluate airway vagal response to intracisternally injected γ-aminobutyric acid (GABA). Immunofluorescent staining and Western-blot assay were used to examine the expression of microglia-specific proteins, Na+-K+-2Cl– co-transporter 1 (NKCC1), K+-Cl– co-transporter 2 (KCC2) and brain-derived nerve growth factor (BDNF) in airway vagal centers. Pulmonary inflammatory changes were examined with hematoxylin and eosin staining of lung sections and ELISA assay of ovalbumin-specific IgE in bronchoalveolar lavage fluid (BALF). The results showed that histochemically, experimental airway allergy activated microglia, upregulated NKCC1, downregulated KCC2, and increased the content of BDNF in airway vagal centers. Functionally, experimental airway allergy augmented the excitatory airway vagal response to intracisternally injected GABA, which was attenuated by intracisternally pre-injected NKCC1 inhibitor bumetanide. All of the changes induced by experimental airway allergy were prevented or mitigated by chronic intracerebroventricular or intraperitoneal injection of minocycline, an inhibitor of microglia activation. These results demonstrate that experimental airway allergy augments the excitatory response of airway vagal centers to GABA, which might be the result of neuronal Cl– dyshomeostasis subsequent to microglia activation, increased BDNF release and altered expression of Cl– transporters. Cl– dyshomeostasis in airway vagal centers might contribute to the genesis of airway vagal hypertonia in asthma.
Highlights
The airway vagal nerves provide the primary cholinergic control to the airway (Canning, 2006)
Compared with the rats from the control group, rats from the OVA group showed decreased pulmonary function, as was manifested by significant decreases in dynamic compliance of the lungs (Cdyn), peak inspiratory flow (PIF), peak expiratory flow (PEF), and significant increases in resistance of the airway (Ri) and resistance of the airway (Re) (Figures 1B–F). All of these changes induced by airway allergy were either attenuated or blocked by minocycline in rats of OVA + MC(ip) and OVA + MC(icv) groups (Figure 1) (n = 10 in each group). These results demonstrate that in rats of experimental airway allergy, minocycline, whether applied peripherally or intracerebroventricularly, can alleviate the pulmonary inflammation and improve pulmonary function, and suggest that the pulmonary function decrease and pulmonary inflammation might be at least in part due to augmented airway vagal activity, which might be subsequent to activation of central microglia
This study found that both Na+-K+2Cl− co-transporter 1 (NKCC1) and K+-Cl− co-transporter 2 (KCC2) are expressed in the nucleus ambiguus (NA) of rats
Summary
The airway vagal nerves provide the primary cholinergic control to the airway (Canning, 2006). It has been well recognized that the onset or exacerbation of asthma is not always accompanied by clear evidence that the alreadysensitized airway vagal reflex is activated by certain triggering factors, such as inhalation of irritants and prompt acceleration of airway inflammation. Typical examples are nocturnal and psychological stress-induced onset or exacerbation of asthma. These phenomena raise a possibility that in asthma, the excitability/responsiveness of AVPNs might have been altered. During night sleep or psychological stress, altered excitability/responsiveness of AVPNs might enable these neurons to trigger the onset or exacerbation of asthma, in response to airway stimuli and, automatically through augmented tonic activity
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