Purinergic Signaling in Early Inflammatory Events of the Foreign Body Response: Modulating Extracellular ATP as an Enabling Technology for Engineered Implants and Tissues

Abstract

Purinergic signaling is a ubiquitous and vital aspect of mammalian biology in which purines-mainly adenosine triphosphate (ATP)-are released from cells through loss of membrane integrity (cell death), exocytosis, or transport/diffusion across membrane channels, and exert paracrine or autocrine signaling effects through three subclasses of well-characterized receptors: the P1 adenosine receptors, the P2X ionotropic nucleotide receptors, and the P2Y metabotropic receptors. ATP and its metabolites are released by damaged and stressed cells in injured tissues. The early events of wound healing, hemostasis, and inflammation are highly regulated by these signals through activation of purinergic receptors on platelets and neutrophils. Recent data have demonstrated that ATP signaling is of particular importance to targeting leukocytes to sites of injury. This is particularly relevant to the subject of implanted medical devices, engineered tissues, and grafts as all these technologies elicit a wound healing response with varying degrees of encapsulation, rejection, extrusion, or destruction of the tissue or device. Here, we review the biology of purinergic signaling and focus on ATP release and response mechanisms that pertain to the early inflammatory phase of wound healing. Finally, therapeutic options are explored, including a new class of peptidomimetic drugs based on the ATP-conductive channel connexin43.

P2X ion channel receptors and inflammation

“…Application of apyrase to CD39-deficient mice prior to ischaemia reduced infarct volumes and neutrophil counts [135,136]. Kinase inhibitors have been recommended for the treatment of inflammatory and autoimmune disorders, such as rheumatoid arthritis, psoriasis, organ transplantation, and autoimmune diseases [137,138].…”

Inhibition of Connexin 43 Hemichannel-Mediated ATP Release Attenuates Early Inflammation During the Foreign Body Response

“…86 Driving this sequence is a web of various autocrine and paracrine cellular signals, with recent evidence pointing to extracellular ATP as an important component in the signaling milieu. 20 This study contributes to this growing body of evidence, with the novel finding that purinergic signaling is a key component of early inflammation during the foreign body response. Moreover, our results show that this response is likely mediated by Cx43 hemichannel release of ATP.…”

“…67 However, connexin hemichannels have been shown to open in response to a variety of stimuli, including mechanical stress and ischemic conditions. 20 Mechanical stress to cellular components of tissues is an unavoidable consequence of injury even in the context of sterile surgical procedures. An in vitro model of mechanical stress by Gomes et al entailed physically depressing the cellular membrane of bovine corneal endothelial cells, known to express Cx43 hemichannels, with a glass pipette, inducing ATP release through connexin hemichannels.…”

“…20,[81][82][83] Once implanted, the actions of the acute immune response jeopardize the integrity of scaffolds and the survival of implanted cells. The clinical success of these constructs depends on adequate delivery and survival of engineered tissues and cells.…”

“…19 Cytokines released by immune cells are widely accepted as key signals in inflammatory processes. 20 However, recent evidence supports a parallel pathway of purinemediated (aka purinergic) signaling as a critical modulator of inflammation. Notably, extracellular ATP has been shown to be a mediator of multiple early inflammatory mechanisms, including neutrophil trafficking.…”