Abstract
Background: Proline-Glycine-Proline (PGP) is a bioactive collagen-derived fragment proteolytically liberated during inflammation, and subsequently able to promote both neutrophil recruitment and epithelial repair. During acute, self-resolving inflammation, PGP is readily degraded by LTA4H to limit its bioavailability. In the chronic lung diseases (CLDs) asthma and COPD, a failure to degrade PGP results in chronic neutrophilia and pathological epithelial remodelling. However, the PGP-LTA4H axis has not been investigated in idiopathic pulmonary fibrosis (IPF) - a CLD characterised by aberrant epithelial repair and ensuing fibrosis.
Methods: The PGP-LTA4H axis was characterised in bronchoalveolar lavage of 69 IPF and 17 control patients, and in a mouse bleomycin model of pulmonary fibrosis. The role of PGP in driving the pathology of bleomycin-induced fibrosis was defined by preventing its degradation (lta4h−/− mice) or via administration of PGP.
Results: Unlike in other CLDs, PGP was undetectable in IPF and in bleomycin treated mice due to overzealous degradation by high levels of LTA4H. Studies in bleomycin treated lta4h−/− mice suggested distinct biphasic roles of the enzyme – limiting neutrophilic inflammation early after bleomycin treatment but enabling aberrant epithelial repair in the fibrotic phase. Accordingly, administration of PGP to bleomycin treated wild type mice during the early phase augmented neutrophilia, while delayed administration of PGP during the late fibrotic phase alleviated pathology.
Conclusions: Overzealous degradation of PGP by LTA4H enables aberrant epithelial repair responses and ensuing pulmonary fibrosis in IPF patients.
Footnotes
Cite this article as ERJ Open Research 2022; 8: Suppl. 8, 127.
This article was presented at the 2022 ERS Lung Science Conference, in session “Poster Session 2”.
This is an ERS Lung Science Conference abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).
- Copyright ©the authors 2022