establishment-mouse-model-with-cough-hypersensitivity-via-inhalation

Establishment of a Mouse Model with Cough Hypersensitivity via Inhalation of Citric Acid

Cough is one of the most common symptoms of many respiratory diseases. Chronic cough significantly impacts quality of life and imposes a considerable ...

Guangzhou Medical University

Chronic cough is a common refractory symptom of various respiratory diseases. However, the neural mechanisms that modulate the cough sensitivity and mediate chronic cough remain elusive. Here, we report that GABAergic neurons in the lateral/ventrolateral periaqueductal gray (l/vlPAG) suppress cough processing via a descending pathway. We found that l/vlPAG neurons are activated by coughing-like behaviors and that tussive agent-evoked coughing-like behaviors are impaired after activation of l/vlPAG neurons. In addition, we showed that l/vlPAG neurons form inhibitory synapses with the nucleus of the solitary tract (NTS) neurons. The synaptic strength of these inhibitory projections is weaker in cough hypersensitivity model mice than in naïve mice. Important, activation of l/vlPAG GABAergic neurons projecting to the NTS decreases coughing-like behaviors. In contrast, suppressing these neurons enhances cough sensitivity. These results support the notion that l/vlPAG GABAergic neurons play important roles in cough hypersensitivity and chronic cough through disinhibition of cough processing at the medullary level.

A descending pathway emanating from the periaqueductal gray mediates the development of cough-like hypersensitivity.

Not all gastroesophageal reflux-induced cough (GERC) patients respond to anti-reflux treatment. It is not certain whether reflux-related symptoms or other clinical characteristics could indicate a successful response to anti-reflux treatment. In this study, we aimed to investigate the relationship between clinical features and anti-reflux response.

Predictive value of clinical features for anti-reflux therapy response in suspected gastroesophageal reflux-induced chronic cough.

Eosinophilic asthma (EA) and non-asthmatic eosinophilic bronchitis (EB) share similar eosinophilic airway inflammation. Unlike EA, EB did not present airway hyperresponsiveness or airflow obstruction. We aimed to compare the mechanism underlying the different manifestations between EA and EB via sputum transcriptomics analysis.

Sputum Transcriptomics Reveals FCN1+ Macrophage Activation in Mild Eosinophilic Asthma Compared to Non-Asthmatic Eosinophilic Bronchitis.

Cough variant asthma (CVA), a common reason for chronic cough, is a globally prevalent and burdensome condition. The heterogeneity of CVA and a lack of knowledge concerning the exact molecular pathogenesis has hampered its clinical management. This study presented the first sputum metabolome of CVA patients, revealed the dynamic change during treatment, and explored biomarkers related to the occurrence and treatment response of CVA. We found arginine biosynthesis, purine metabolism, and pyrimidine metabolism pathways were enriched in CVA compared to healthy controls. Part of metabolic disturbances could be reversed by anti-asthmatic medication. The levels of dipeptides/tripeptides (alanyltyrosine, Gly-Tyr-Ala, Ala-Leu, and Thr-Leu) were significantly associated with sputum Neu% or Eos% of CVA patients. Differential metabolites pre-treatment between effective and ineffective groups enriched in purine metabolism, thiamine metabolism, and arginine metabolism. 2-isopropylmalate was down-regulated in CVA patients and increased after treatment, and effective group had a lower 2-isopropylmalate level pre-treatment. Random forest and logistic regression models identified glutathione, thiamine phosphate, alanyltyrosine, and 2'-deoxyadenosine as markers for distinguishing CVA from healthy controls (all AUC > 0.8). Thiamine phosphate might also be promising for predicting therapy responsiveness (AUC = 0.684). These findings implied that disturbed mitochondrial energy metabolism and imbalanced oxidation-reduction homeostasis probably underlay the metabolic pathogenesis of CVA.

Sputum Metabolomic Signature and Dynamic Change of Cough Variant Asthma.

It has been reported that experimental pain could diminish cough sensitivity, the lateral parabrachial nucleus (LPBN) coordinated pain with breathing, whether LPBN regulates cough-like behaviors and pain-induced changes in cough sensitivity remains elusive. We investigated the roles of LPBN γ-aminobutyric acidergic (GABAergic) and glutamatergic neurons in the regulation of cough sensitivity and its relationship with pain in mice via chemogenetic approaches. Adeno-associated virus (AAV) tracing combined with chemogenetics was used to map the projections of LPBN GABAergic and glutamatergic neurons to the periaqueductal gray (PAG). LPBN neurons were activated by cough challenge, and nonspecific inhibition of LPBN neurons suppressed cough-like behavior. Chemogenetic suppression of LPBN GABAergic neurons reduced cough sensitivity in mice, whereas suppression of LPBN glutamatergic neurons counteracted the pain-driven decrease in cough sensitivity, so did silencing LPBN glutamatergic neurons projecting to the PAG. Our data suggest that GABAergic and glutamatergic neurons in the LPBN critically are involved in cough sensitivity and coordinate pain with cough through inhibitory or activating mechanisms at the midbrain level.

Multiple Neural Networks Originating from the Lateral Parabrachial Nucleus Modulate Cough-like Behavior and Coordinate Cough with Pain.

The study aimed to examine the impact of melatonin on mitigating brain inflammation and cough sensitivity resulting from exposure to particulate matter 2.5 (PM2.5).

Article	Year
A descending pathway emanating from the periaqueductal gray mediates the development of cough-like hypersensitivity. iScience\| PubMed ID: 35028531	2022
Predictive value of clinical features for anti-reflux therapy response in suspected gastroesophageal reflux-induced chronic cough. Journal of thoracic disease\| PubMed ID: 37197530	2023
Sputum Transcriptomics Reveals FCN1+ Macrophage Activation in Mild Eosinophilic Asthma Compared to Non-Asthmatic Eosinophilic Bronchitis. Allergy, asthma & immunology research\| PubMed ID: 38262391	2024
Sputum Metabolomic Signature and Dynamic Change of Cough Variant Asthma. American journal of respiratory cell and molecular biology\| PubMed ID: 39393348	2024
Multiple Neural Networks Originating from the Lateral Parabrachial Nucleus Modulate Cough-like Behavior and Coordinate Cough with Pain. American journal of respiratory cell and molecular biology\| PubMed ID: 39417744	2024
Melatonin inhibits the activation of microglia and cough sensitivity of guinea pigs exposed to PM2.5. Histology and histopathology\| PubMed ID: 39659195	2024

Mingtong Lin

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