Purinergic signaling in scarring.
Adenosine (ADO) and nucleotides such as ATP, ADP, and uridine 5'-triphosphate (UTP), among others, may serve as extracellular signaling molecules. These mediators activate specific cell-surface receptors-namely, purinergic 1 and 2 (P1 and P2)-to modulate crucial pathophysiological responses. Regulation of this process is maintained by nucleoside and nucleotide transporters, as well as the ectonucleotidases ectonucleoside triphosphate diphosphohydrolase [ENTPD; cluster of differentiation (CD)39] and ecto-5'-nucleotidase (5'-NT; CD73), among others. Cells involved in tissue repair, healing, and scarring respond to both ADO and ATP. Our recent investigations have shown that modulation of purinergic signaling regulates matrix deposition during tissue repair and fibrosis in several organs. Cells release adenine nucleotides into the extracellular space, where these mediators are converted by CD39 and CD73 into ADO, which is anti-inflammatory in the short term but may also promote dermal, heart, liver, and lung fibrosis with repetitive signaling under defined circumstances. Extracellular ATP stimulates cardiac fibroblast proliferation, lung inflammation, and fibrosis. P2Y2 (UTP/ATP) and P2Y6 [ADP/UTP/uridine 5'-diphosphate (UDP)] have been shown to have profibrotic effects, as well. Modulation of purinergic signaling represents a novel approach to preventing or diminishing fibrosis. We provide an overview of the current understanding of purinergic signaling in scarring and discuss its potential to prevent or decrease fibrosis.
*Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Department of Pneumology, University of Freiburg, Freiburg, Germany; Laboratory of Immunology and Laboratory of Tissue Engineering and Cutaneous Physiopathology, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Department of Specialized, Diagnostic, and Experimental Medicine, University of Bologna, Bologna, Italy; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, USA; and Department of Medicine, New York University, New York, New York, USA dfr@unife.it.
Davide
D
Ferrari
*Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Department of Pneumology, University of Freiburg, Freiburg, Germany; Laboratory of Immunology and Laboratory of Tissue Engineering and Cutaneous Physiopathology, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Department of Specialized, Diagnostic, and Experimental Medicine, University of Bologna, Bologna, Italy; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, USA; and Department of Medicine, New York University, New York, New York, USA.
Roberto
R
Gambari
*Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Department of Pneumology, University of Freiburg, Freiburg, Germany; Laboratory of Immunology and Laboratory of Tissue Engineering and Cutaneous Physiopathology, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Department of Specialized, Diagnostic, and Experimental Medicine, University of Bologna, Bologna, Italy; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, USA; and Department of Medicine, New York University, New York, New York, USA.
Marco
M
Idzko
*Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Department of Pneumology, University of Freiburg, Freiburg, Germany; Laboratory of Immunology and Laboratory of Tissue Engineering and Cutaneous Physiopathology, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Department of Specialized, Diagnostic, and Experimental Medicine, University of Bologna, Bologna, Italy; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, USA; and Department of Medicine, New York University, New York, New York, USA.
Tobias
T
Müller
*Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Department of Pneumology, University of Freiburg, Freiburg, Germany; Laboratory of Immunology and Laboratory of Tissue Engineering and Cutaneous Physiopathology, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Department of Specialized, Diagnostic, and Experimental Medicine, University of Bologna, Bologna, Italy; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, USA; and Department of Medicine, New York University, New York, New York, USA.
Cristina
C
Albanesi
*Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Department of Pneumology, University of Freiburg, Freiburg, Germany; Laboratory of Immunology and Laboratory of Tissue Engineering and Cutaneous Physiopathology, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Department of Specialized, Diagnostic, and Experimental Medicine, University of Bologna, Bologna, Italy; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, USA; and Department of Medicine, New York University, New York, New York, USA.
Saveria
S
Pastore
*Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Department of Pneumology, University of Freiburg, Freiburg, Germany; Laboratory of Immunology and Laboratory of Tissue Engineering and Cutaneous Physiopathology, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Department of Specialized, Diagnostic, and Experimental Medicine, University of Bologna, Bologna, Italy; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, USA; and Department of Medicine, New York University, New York, New York, USA.
Gaetano
G
La Manna
*Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Department of Pneumology, University of Freiburg, Freiburg, Germany; Laboratory of Immunology and Laboratory of Tissue Engineering and Cutaneous Physiopathology, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Department of Specialized, Diagnostic, and Experimental Medicine, University of Bologna, Bologna, Italy; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, USA; and Department of Medicine, New York University, New York, New York, USA.
Simon C
SC
Robson
*Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Department of Pneumology, University of Freiburg, Freiburg, Germany; Laboratory of Immunology and Laboratory of Tissue Engineering and Cutaneous Physiopathology, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Department of Specialized, Diagnostic, and Experimental Medicine, University of Bologna, Bologna, Italy; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, USA; and Department of Medicine, New York University, New York, New York, USA.
Bruce
B
Cronstein
D000241:Adenosine / Q000378:metabolism; D000818:Animals; D005355:Fibrosis / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D058905:Purinergic Agents / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014544:Uridine Triphosphate / Q000378:metabolism*
D058905:Purinergic Agents; D000241:Adenosine; D014544:Uridine Triphosphate
COPD; Crohn’s disease; adenosine; extracellular nucleotides; fibrosis