endothelin-1 and Pseudomonas-Infections

Direct recognition of invading pathogens by innate immune cells is a critical driver of the inflammatory response. However, cells of the innate immune system can also sense their local microenvironment and respond to physiological fluctuations in temperature, pH, oxygen and nutrient availability, which are altered during inflammation. Although cells of the immune system experience force and pressure throughout their life cycle, little is known about how these mechanical processes regulate the immune response. Here we show that cyclical hydrostatic pressure, similar to that experienced by immune cells in the lung, initiates an inflammatory response via the mechanically activated ion channel PIEZO1. Mice lacking PIEZO1 in innate immune cells showed ablated pulmonary inflammation in the context of bacterial infection or fibrotic autoinflammation. Our results reveal an environmental sensory axis that stimulates innate immune cells to mount an inflammatory response, and demonstrate a physiological role for PIEZO1 and mechanosensation in immunity.

Topics: Animals; Endothelin-1; Female; Hydrostatic Pressure; Hypoxia-Inducible Factor 1, alpha Subunit; Immunity, Innate; Inflammation; Ion Channels; JNK Mitogen-Activated Protein Kinases; Lung; Macrophages; Male; Mechanotransduction, Cellular; Mice; Pseudomonas aeruginosa; Pseudomonas Infections; Signal Transduction

Endothelin (ET)-1 has been suggested to promote neutrophil adhesion to endothelium, migration to inflamed areas, and release of elastase. ET-1 might therefore play a role in the pathogenesis of bronchiectasis, a chronic inflammatory and infective airway disease which is still poorly understood. Thirty five patients with stable bronchiectasis (20 females, mean age+/-SD 49.1+/-15.0 yrs) and 18 control subjects (8 females, 49.4+/-11.3 yrs) were recruited prospectively. The ET-1 levels in serum and sputum were measured by commercially available enzyme linked immunosorbent assay (ELISA) kits. Patients with Pseudomonas aeruginosa in their sputum had a significantly higher serum level of ET-1 (median 25.8, interquartile range 13-43.9 pg x mL(-1)) than patients without P. aeruginosa (0, 0-10.5 pg x mL(-1); p=0.0004) and healthy control subjects (4.6, 0-16.3 pg x mL(-1); p=0.002). However, patients with and without P. aeruginosa infection had no significant difference in sputum ET-1 level (p=0.15). There was no correlation between serum or sputum ET-1 levels with the serum and sputum levels of the interleukin (IL)-1beta, IL-8 and tumour necrosis factor (TNF)-alpha; the number of bronchiectasis lung lobes; and spirometry. Serum ET-1 level correlated with 24 h sputum volume for the bronchiectasis patients (r=0.51, p=0.002). The results, therefore, suggest a significant pathogenic role for endothelin-1 among Pseudomonas aeruginosa-infected patients with bronchiectasis. Further studies should be performed to evaluate the clinico-pathological correlation and expression of endothelin-1 in bronchiectasis.

Topics: Bronchiectasis; Endothelin-1; Female; Humans; Interleukin-1; Interleukin-8; Leukocytes; Male; Middle Aged; Pancreatic Elastase; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Sputum; Tumor Necrosis Factor-alpha

Topics: Cell Hypoxia; Culture Techniques; Endothelin-1; Endothelium, Vascular; Humans; Hypertension, Pulmonary; Nitric Oxide; Nitric Oxide Synthase; Organ Culture Techniques; Pneumonia; Pseudomonas Infections; Pulmonary Heart Disease