The autotaxin-lysophosphatidic acid pathway mediates mesenchymal cell recruitment and fibrotic contraction in lung transplant fibrosis.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the leading cause of mortality in lung transplant recipients. CLAD is characterized by respiratory failure owing to the accumulation of fibrotic cells in small airways and alveoli, inducing tissue contraction and architectural destruction. However, the source of the fibroblastic cells and the mechanism(s) underlying the accumulation and activation remain unexplained. Mesenchymal stromal cells (MSCs) are multipotent progenitors that are normally located in the lung tissue but can be isolated from the alveolar space in lung transplant recipients, where they have a profibrotic phenotype. Our objective was to identify the mediator(s) inducing migration and contractile differentiation of lung tissue MSCs. METHODS: Bronchoalveolar lavage (BAL) (7 healthy controls and 21 lung transplant recipients), CCL2, HGF, TGFB, EGF, and PDGF-BB and autotaxin were measured by enzyme-linked immunosorbent assay. BAL (7 healthy controls and 31 lung transplant recipients) lysophosphatidic acid (LPA) (16:0, 18:0, 18:1, 22:4) was measured by liquid chromatography with tandem mass spectrometry. The effect of inhibition of candidate mediators on BAL-mediated chemoattraction of MSCs and contraction of MSC-spiked collagen gel assays was assessed. BAL cells from a lung transplant recipient with CLAD were analyzed by single-cell RNA sequencing. RESULTS: We first demonstrate that BAL fluid from lung transplant recipients and particularly those with CLAD is potently chemoattractive to human lung tissue‒derived MSCs and induces a contractile phenotype. After excluding several candidate mediators, we show that LPA blockade completely abrogated transplant recipient BAL‒mediated chemoattraction of MSCs and contraction of MSC-spiked collagen gels. Furthermore, LPA levels were enriched in transplant recipient BAL, and LPA replicated the observed in vitro profibrotic effects of transplant recipient BAL. Finally, we identify BAL monocyte‒derived macrophages with autotaxin (ENPP2) and fibrotic transcriptional signature. CONCLUSIONS: Autotaxin-expressing alveolar macrophages are present in CLAD BAL. These cells potentially provide a local source of autotaxin/LPA that drives MSC recruitment and tissue contraction in CLAD. These cells are analogous to an aberrant macrophage population recently identified in idiopathic pulmonary fibrosis, suggesting an overlap in pathogenesis between CLAD and other forms of lung fibrosis.

A web- and case-based learning program for postgraduate students in occupational medicine.

Many Belgian postgraduate students in occupational medicine already work in the field although they have had little training or experience. To direct their learning in line with professional needs, an interactive web-based program was developed and evaluated. On-line multiple-choice questions and real-life cases were used as an add-on to the master course in occupational medicine. Students' perceptions were obtained by questionnaire. Trainees felt that the multiple-choice questions with immediate feedback and automatic scoring increased their factual knowledge. The case studies were well received because they were realistic and of appropriate difficulty level. Students preferred the combination of face-to-face teaching and e-learning to a whole course online and were in favor of more active communication between teachers and users. These findings may inform further collaborative developments in educational technology in occupational health.