Background/Purpose: Interstitial lung diseases with an autoimmune background (AIP) are a heterogeneous group of processes. There is an unmet need to identify those cases with a progressive fibrosing phenotype in order to tailor therapeutics. Both of inflammation and hypoxia enhance ATP externalisation and increase synthesis of extracellular adenosine. In turn, increased adenosine promotes postinjury fibrotic remodelling, via A2A or A2B receptors. Netrin-1, which is also triggered by hypoxia has been found to activate A2B receptors, and is up-regulated during experimental and human lung fibrosis. We have explored activation of the adenosine pathway in patients with different subtypes of AIP.

Methods: We conducted a cross-sectional study in patients from the NEREA Register of autoimmune IP cases and in lung tissues from the IIS-HUFJD biobank. We measured adenosine and its metabolite inosine in plasma using HPLC. Serum levels of netrin 1 were determined by ELISA. Immunodetection of A2A, A2B and alpha-SMA was performed in the lung specimens. A descriptive analysis was carried out, and comparison between categories was done with parametric tests.

Results: The population comprised 126 subjects (115 cases, 74% women, and 11 controls). There were 64 newly diagnosed patients and 51 prevalent cases. Predominant radiographic patterns were NSIP (32p) and UIP (23p), while underlying autoimmune conditions included 9p with RA, 5 MCTD, 4 ARS, 16 SSc, 6 pSS, 3 IIM, and overlapping syndromes. Twenty six patients fulfilled IPAF criteria, while 11 patients were unclassifiable. At the time of biomarkers determination, 44p were considered to have a fibrotic process. Presence of RA-defining autoAb was found in 24 patients. ANA test was + in 69 out of 81 cases. There was a positive correlation between adenosine and netrin 1 (r 0.3, p 0.004), but not with the markers of epithelial injury lactate dehydrogenase (LDH) and Krebs von den Lungen 6 (KL6). Netrin 1 was enhanced in the patient population in comparison to healthy controls (p 0.005). Levels of adenosine, inosine and netrin 1 were higher in women than in men, and also tended to be higher in patients with established disease as compared with newly diagnosed ones, while in contrast KL-6 levels dropped in established disease as regarded to newly diagnosed patients (p 0.05). Netrin 1 levels were higher in those patients with fibrotic disease (p 0.08), and in RF+ cases (p 0.011). In contrast, we could not observe significant differences as concerned radiographic patterns or clinical diagnosis.
In the lung specimens, A2B receptors were enriched at the fibrotic interstitial areas and in alveolar epithelial cells. On the other hand, scattered infiltrating cells and some endothelial layers showed activation of the A2A receptors.

Conclusion: On the whole, our findings suggest that a subgroup or patients with AIP up-regulate the adenosine/netrin-1 pathway, in this way promoting the development of a profibrotic remodelling via A2BR and possibly modulating processes of immune cell activation and migration via A2A signaling. The role of netrin 1 as biomarker of the progressive fibrosing phenotype in these patients needs to be confirmed with longitudinal studies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/could-the-adenosine-pathway-identify-cases-with-a-progressive-fibrosing-phenotype-between-patients-with-autoimmune-interstitial-lung-disease-an-initial-approach/