RESUMO
Liver fibrosis is the consequence of chronic liver injury in the presence of an inflammatory component. Although the main executors of this activation are known, the mechanisms that lead to the inflammatory process that mediates the production of pro-fibrotic factors are not well characterized. Epidermal growth factor receptor (EGFR) signaling in hepatocytes is essential for the regenerative processes of the liver; however, its potential role in regulating the fibrotic niche is not yet clear. Our group generated a mouse model that expresses an inactive truncated form of the EGFR specifically in hepatocytes (ΔEGFR mice). Here, we have analyzed the response of WT and ΔEGFR mice to chronic treatment with carbon tetrachloride (CCl4), which induces a pro-inflammatory and fibrotic process in the liver. The results indicated that the hallmarks of liver fibrosis were attenuated in CCl4-treated ΔEGFR mice when compared with CCl4-treated WT mice, coinciding with a faster resolution of the fibrotic process and ameliorated damage. The absence of EGFR activity in hepatocytes induced changes in the pattern of immune cells in the liver, with a notable increase in the population of M2 macrophages, more related to fibrosis resolution, as well as in the population of lymphocytes related to eradication of the damage. Transcriptome analysis of hepatocytes, and secretome studies of extracellular media from in vitro experiments, allowed us to elucidate the specific molecular mechanisms regulated by EGFR that mediate hepatocyte production of both pro-fibrotic and pro-inflammatory mediators; these have consequences for the deposition of extracellular matrix proteins, as well as for the immune microenvironment. Overall, our study uncovered novel mechanistic insights regarding EGFR kinase-dependent actions in hepatocytes that reveal its key role in chronic liver damage. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
RESUMO
Essential Biodiversity Variables (EBVs) allow observation and reporting of global biodiversity change, but a detailed framework for the empirical derivation of specific EBVs has yet to be developed. Here, we re-examine and refine the previous candidate set of species traits EBVs and show how traits related to phenology, morphology, reproduction, physiology and movement can contribute to EBV operationalization. The selected EBVs express intra-specific trait variation and allow monitoring of how organisms respond to global change. We evaluate the societal relevance of species traits EBVs for policy targets and demonstrate how open, interoperable and machine-readable trait data enable the building of EBV data products. We outline collection methods, meta(data) standardization, reproducible workflows, semantic tools and licence requirements for producing species traits EBVs. An operationalization is critical for assessing progress towards biodiversity conservation and sustainable development goals and has wide implications for data-intensive science in ecology, biogeography, conservation and Earth observation.
