Purinergic Signaling in Wound Healing and Airway Remodeling

Abstract

Airway epithelia are continuously damaged by airborne pollutants, pathogens and allergens, and they rely on intrinsic mechanisms to restore barrier integrity. Epithelial repair is a multi-step process including cell migration into the wounded area, proliferation, differentiation and matrix deposition. Each step requires the secretion of various molecules, including growth factors, integrins and matrix metalloproteinases. Evidence is emerging that purinergic signaling promotes repair in human airway epithelia. An injury induces ATP release, which binds P2Y(2) receptors (P2Y(2)Rs) to initiate protein kinase C (PKC)-dependent oxidative activation of TNFα-converting enzyme (TACE), which then releases the membrane-bound ligands of the epidermal growth factor receptor (EGFR). The P2Y(2)R- and EGFR-dependent signaling cascades converge to induce mediator release, whereas the latter also induces cytoskeletal rearrangement for cell migration and proliferation. Similar roles for purinergic signaling are reported in pulmonary endothelial cells, smooth muscle cells and fibroblasts. In chronic airway diseases, the aberrant regulation of extracellular purines is implicated in the development of airway remodeling by mucus cell metaplasia and hypersecretion, excess collagen deposition, fibrosis and neovascularization. This chapter describes the crosstalk between these signaling cascades and discusses the impact of deregulated purinergic signaling in chronic lung diseases.

Hydrogen Peroxide as a Damage Signal in Tissue Injury and Inflammation: Murderer, Mediator, or Messenger?

“…Cellular release of ATP is readily provoked by mechanical stimuli including shear stress as well as various chemical and biological triggers, either through vesicular release pathways or passive release to connexin or pannexin hemichannels, generating extracellular ATP concentrations sufficient to act as autocrine or paracrine transmitters through activation of purinergic P2Y and P2X receptors on the cell surface and stimulation of cellular signaling pathways that control wound responses [13]. Activation of P2Y receptors (G protein-coupled receptors) and P2X receptors (which act as ligand-gated ion channels) can induce intracellular Ca 2+ increases as a part of their signaling mechanism [13], and conversely, Ca 2+ -dependent signaling mechanisms can also contribute to promoting ATP release [11], thus illustrating a close and reciprocal relationship between these two danger signals.…”

Purinergic signaling in scarring

“…P2Y receptors are involved in the repair of human airway epithelia. The P2Y 2 subtype induces TNFα‐converting enzyme activation, which then releases the membrane‐bound ligands of the epidermal growth factor receptor, thus inducing cell migration and proliferation (49, 55). However, P2Y receptor signaling is most likely also involved in lung fibrosis, as in vitro stimulation of human lung fibroblasts by nucleotides increases the expression of P2Y 4 , TGF‐β, collagen A 1 , and fibronectin (55).…”

“…The P2Y 2 subtype induces TNFα‐converting enzyme activation, which then releases the membrane‐bound ligands of the epidermal growth factor receptor, thus inducing cell migration and proliferation (49, 55). However, P2Y receptor signaling is most likely also involved in lung fibrosis, as in vitro stimulation of human lung fibroblasts by nucleotides increases the expression of P2Y 4 , TGF‐β, collagen A 1 , and fibronectin (55). ADO receptors are expressed in the lung, where they regulate inflammation and airway remodeling by favoring differentiation of lung fibroblasts into myofibroblasts that are typically found in fibrotic tissues (56).…”

“…It has become clear that excessive ligand‐mediated activation of specific nucleoside and nucleotide receptor subtypes as a consequence of uncontrolled ligand release gives the tissue microenvironment a surplus of signals, promoting abnormal replication of smooth muscle cells, fibroblasts, and myofibroblasts, with pathologic matrix deposition causing fibrosis. Recent reports demonstrate the significant contribution of extracellular nucleosides and nucleotides in promoting abnormal matrix production (8, 55, 62). However, at present, this field is at an initial stage and many developments have still to be made.…”

Elevated uric acid correlates with wound severity

“…Cell rupture as a consequence of mechanical or chemical disturbance results in the release of adenosine triphosphate (ATP) into the extracellular environment (12). ATP breaks down in a stepwise fashion to adenosine monophosphate, inosine monophosphate, adenosine, inosine and hypoxanthine, resulting in the accumulation of these metabolites in tissue (13).…”