Dynamic purine signaling and metabolism during neutrophil–endothelial interactions

Abstract

During episodes of hypoxia and inflammation, polymorphonuclear leukocytes (PMN) move into underlying tissues by initially passing between endothelial cells that line the inner surface of blood vessels (transendothelial migration, TEM). TEM creates the potential for disturbances in vascular barrier and concomitant loss of extravascular fluid and resultant edema. Recent studies have demonstrated a crucial role for nucleotide metabolism and nucleoside signaling during inflammation. These studies have implicated multiple adenine nucleotides as endogenous tissue protective mechanisms in vivo. Here, we review the functional components of vascular barrier, identify strategies for increasing nucleotide generation and nucleoside signaling, and discuss potential therapeutic targets to regulate the vascular barrier during inflammation.Abbreviations: AMP -5 0 -adenosine monophosphate; APCP -5 0

Coupled Nucleotide and Mucin Hypersecretion from Goblet-Cell Metaplastic Human Airway Epithelium

“…However, the cellular origins of increased mucus production and inflammatory signals that produce the postviral syndrome have not been unambiguously identified. The current study demonstrated that RSV induces goblet cell metaplasia in HBE cultures, which not only provides a source of increased mucin secretion but also increases ASL nucleotides and nucleosides that may participate in inflammatory signaling (Figures 1 and 2) (42)(43)(44)(45)(46)(47)(48)(49)(50).…”

“…The increase in goblet-cell nucleotide release proportional to increased mucin secretion may provide a compensatory mechanism to hydrate newly secreted mucus and promote airway surface clearance. In parallel, increased release into the extracellular environment of adenine nucleotides and nucleosides may promote airway luminal inflammatory responses via purinoceptors by stimulating secretion of inflammatory mediators from airway epithelia (42)(43)(44), secretion of airway and alveolar fluids (19,45), mucin gene transcription (43,46), neutrophil migration (47,48), and regulating endothelial barrier function (49,50). Accordingly, goblet cell-mediated increases in ATP, adenosine, and UDP-glucose concentrations in airway lumens may coordinately activate innate host defense mucociliary clearance and cellular inflammatory pathways.…”

Cardioprotection by Ecto-5′-Nucleotidase (CD73) and A 2B Adenosine Receptors

“…All 4 ARs have been associated with tissue protection in a variety of physiological settings. 1,10,11 Although all 4 ARs are expressed in cardiac tissues, 12 the contribution of individual receptors to cardioprotection from ischemia and reperfusion remains controversial 13,14 and may in part be related to a lack of studies in which all 4 AR gene-targeted mice are subjected to the same IP protocol in parallel.…”

Physiological Roles of Vascular Nucleoside Transporters

“…[11][12][13]18,[87][88][89][90] Moreover, hypoxiainduced repression of NTs contributes to increasing vascular adenosine levels and signaling effects. These adaptive responses represent innate metabolic and transcriptional pathways to reduce vascular leakage associated with hypoxia and to attenuate the inflammatory response.…”