Cell to Cell Communication in Response to Mechanical Stress via Bilateral Release of ATP and UTP in Polarized Epithelia

• Published in: The Journal of cell biology 2000-09, Vol.150 (6), p.1349-1359
• Main Authors: Homolya, László, Steinberg, Thomas H., Boucher, Richard C.
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Animals; Apyrase - pharmacology; Biological Transport - drug effects; Biological Transport - physiology; Bronchi - cytology; Calcium; Calcium - metabolism; Cell Communication - physiology; Cell lines; Cell Polarity - physiology; Cells; Cells, Cultured; Cellular biology; Cultured cells; Epithelial cells; Epithelial Cells - cytology; Epithelial Cells - metabolism; Hepatocytes; Humans; Image Processing, Computer-Assisted; Mice; Mice, Knockout; Neuroglia; Nucleotides; Original; Receptors; Receptors, Purinergic P2 - genetics; Receptors, Purinergic P2 - metabolism; Receptors, Purinergic P2Y2; Respiratory Mucosa - cytology; Respiratory Mucosa - metabolism; Respiratory system; Stress, Mechanical; Uridine Triphosphate - metabolism; Wave mechanics; Wave propagation
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.150.6.1349

Airway epithelia are positioned at the interface between the body and the environment, and generate complex signaling responses to inhaled toxins and other stresses. Luminal mechanical stimulation of airway epithelial cells produces a propagating wave of elevated intracellular Ca2+that coordinates components of the integrated epithelial stress response. In polarized airway epithelia, this response has been attributed to IP3permeation through gap junctions. Using a combination of approaches, including enzymes that destroy extracellular nucleotides, purinergic receptor desensitization, and airway cells deficient in purinoceptors, we demonstrated that Ca2+waves induced by luminal mechanical stimulation in polarized airway epithelia were initiated by the release of the 5′ nucleotides, ATP and UTP, across both apical and basolateral membranes. The nucleotides released into the extracellular compartment interacted with purinoceptors at both membranes to trigger Ca2+mobilization. Physiologically, apical membrane nucleotide-release coordinates airway mucociliary clearance responses (mucin and salt, water secretion, increased ciliary beat frequency), whereas basolateral release constitutes a paracrine mechanism by which mechanical stresses signal adjacent cells not only within the epithelium, but other cell types (nerves, inflammatory cells) in the submucosa. Nucleotide-release ipsilateral and contralateral to the surface stimulated constitutes a unique mechanism by which epithelia coordinate local and distant airway defense responses to mechanical stimuli.