Discussion
IPF lungs, AE-IPF, fibrosis, IPF
DISEASE PROGRESSION, VASCULAR INFLAMMATION, FIBROSIS, PATHOGENESIS, ENDOTHELIAL DYSFUNCTION
In this study, we identified a number of LPA and TAG species that were significantly dysregulated in patients with IPF. Majority of these lipid species were prognostic of clinical and radiographic outcomes including DLCO decline, exacerbation or respiratory hospitalization, mortality, and fibrosis increase in the lower lungs. Since this study included a subset of patients reported previously (IPF lungs have elevated levels of lipid palmitic acid (C16:0) compared to controls (Systemic LPA could also originate from macrophages or inflammatory cells in the form of vesicles (LPA can bind to non-G-protein-coupled receptors such as RAGE to mediate vascular inflammation and platelet activation (YKL40 serum levels and gene expression in the lungs were higher in patients with IPF compared to healthy controls (Among the protein biomarkers identified to be prognostic of disease progression by Clynick B A growing body of evidence implicates the role of increased alveolar-capillary permeability and endothelial dysfunction in IPF pathogenesis (The distribution of fibrosis in IPF lungs has been linked to acute exacerbation and mortality (The reasons why LPA and TAG species were prognostic of some but not all of the clinical and radiographic outcomes in this study remain unclear. LPA mediates the downstream signaling through receptor activation where six LPA receptors have been characterized that are expressed at different levels on different cell types (The study has a number of limitations. First, this was a post hoc analysis of a clinical trial and sampling was incomplete. However, the demographics captured were representative of the overall placebo population. Second, we prioritized lipids with at least a twofold difference compared to healthy for clinical analyses; the differences in some of the clinical outcomes were based on the median level of the LPA and TAG used to subgroup patients, additional work is needed to assess the optimal cutoffs. Finally, the relationship between systemic LPA levels and the lung compartment has not been examined as lung sampling was not collected in this study.In summary, we identified plasma LPA and TAG species that were significantly dysregulated in IPF patients; these LPA and TAG species were prognostic of clinical outcomes but only LPA species were independent prognostic biomarkers of DLCO decline and fibrosis increase in the lung. Further work is needed to understand the mechanistic processes underlying these observations. IPF has a poor prognosis and patients with AE-IPF reportedly have increased mortality and morbidity. The discovery of these biomarkers may aid in the early identification of high-risk patients with rapid disease progression, which is imperative to prompt the initiation of appropriate treatments to preserve lung function.