The sensory irritant receptor TRPA1 is essential for airway inflammation in the LPS mouse model of acute lung injury
| Autor: | Ana Isabel Caceres, Sven-Eric Jordt |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
ARDS
Chemokine Lung biology Lipopolysaccharide business.industry medicine.medical_treatment food and beverages Inflammation respiratory system Lung injury medicine.disease respiratory tract diseases Pathogenesis chemistry.chemical_compound medicine.anatomical_structure Cytokine chemistry Immunology biology.protein Medicine medicine.symptom business psychological phenomena and processes |
| Zdroj: | Airway pharmacology and treatment. |
| DOI: | 10.1183/13993003.congress-2019.pa3885 |
| Popis: | Lung infection by Gram-negative bacteria is a major cause of morbidity and mortality in humans. LPS (lipopolysaccharide), a component of Gram-negative bacterial cell walls, plays a major role in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Experimental endotoxin (LPS) administered intranasally in mice has been extensively used to study the pathogenesis of ALI/ARDS. TRPA1 is an irritant-sensing ion channel expressed in airway chemosensory nerves. TRPA1-activating stimuli include cigarette smoke, chlorine, irritants, aldehydes and scents. Endogenous and exogenous TRPA1 agonists, including reactive oxygen species and lipid peroxidation products, are potent drivers of inflammatory conditions in the lung. We examined the role of TRPA1 in the LPS mouse model of ALI. 24 hr after LPS intranasal instillation in the mice, lungs and bronchoalvelolar lavage (BAL) were collected and analyzed by qPCR, Luminex and cell counting among other techniques. Genetic ablation of TRPA1 reduced LPS-induced leukocyte infiltration, cytokine/chemokine production and MPO activity in the lungs. This phenotype was recapitulated by treatment of wild-type mice with two different TRPA1 antagonists: HC030031 and A967079. These TRPA1 blockers when administered before and after the LPS challenge, inhibited neutrophil infiltration and prevented lung inflammation significantly. Our data suggest that TRPA1 is a key integrator of interactions between the immune and nervous systems in the airways, driving the lung injury following inhaled LPS challenge. TRPA1 may represent a promising pharmacological target for the treatment of ALI, ARDS and other pulmonary inflammatory conditions. |
| Databáze: | OpenAIRE |
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