When healing turns into killing – the pathophysiology of pancreatic and hepatic fibrosis

Ferdek, Paweł; Krzysztofik, Daria; Stopa, Kinga B; Kusiak, Agnieszka A.; Paw, Milena; Wnuk, Dawid; Jakubowska, Monika A.

doi:10.1113/jp281135

Cited by 12 publications

(10 citation statements)

References 360 publications

(430 reference statements)

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“…The gene ontology analysis of these data revealed a clear picture of disease progression involving disruption in cell migration and cell adhesion processes that ultimately produce a prolonged wound healing response. This has been observed in other fibrotic disorders in the liver and other tissues 22-24 . Loss of PKHD1 in PCK rat livers triggers an injury response that is not typical in the sense of structural damage or functional damage but seems to be associated with disruption of normal bile duct development.…”

Section: Discussionsupporting

confidence: 63%

Global Transcriptomics of Congenital Hepatic Fibrosis in Autosomal Recessive Polycystic Kidney Disease using PCK rats

Khare

Jiang

Cabrera

et al. 2023

Preprint

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Congenital hepatic fibrosis / Autosomal recessive polycystic kidney disease (CHF/ARPKD) is an inherited neonatal disease induced by mutations in the PKHD1 gene and characterized by cysts, and robust pericystic fibrosis in liver and kidney. The PCK rat is an excellent animal model which carries a Pkhd1 mutation and exhibits similar pathophysiology. We performed RNA-Seq analysis on liver samples from PCK rats over a time course of postnatal day (PND) 15, 20, 30, and 90 using age-matched Sprague-Dawley (SD) rats as controls to characterize molecular mechanisms of CHF/ARPKD pathogenesis. A comprehensive differential gene expression (DEG) analysis identified 1298 DEGs between PCK and SD rats. The genes overexpressed in the PCK rats at PND 30 and 90 were involved cell migration (e.g. Lamc2, Tgfb2, and Plet1), cell adhesion (e.g. Spp1, Adgrg1, and Cd44), and wound healing (e.g. Plat, Celsr1, Tpm1). Connective tissue growth factor (Ctgf) and platelet-derived growth factor (Pdgfb), two genes associated with fibrosis, were upregulated in PCK rats at all time-points. Genes associated with MHC class I molecules (e.g. RT1-A2) or involved in ribosome assembly (e.g. Pes1) were significantly downregulated in PCK rats. Upstream regulator analysis showed activation of proteins involved tissue growth (MTPN ) and inflammation (STAT family members) and chromatin remodeling (BRG1), and inhibition of proteins involved in hepatic differentiation (HNF4alpha) and reduction of fibrosis (SMAD7). The increase in mRNAs of four top upregulated genes including Reg3b, Aoc1, Tm4sf20, and Cdx2 was confirmed at the protein level using immunohistochemistry. In conclusion, these studies indicate that a combination of increased inflammation, cell migration and wound healing, and inhibition of hepatic function, decreased antifibrotic gene expression are the major underlying pathogenic mechanisms in CHF/ARPKD.

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Section: Discussionsupporting

confidence: 63%

Global Transcriptomics of Congenital Hepatic Fibrosis in Autosomal Recessive Polycystic Kidney Disease using PCK rats

Khare

Jiang

Cabrera

et al. 2023

Preprint

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“…Hepatotropic viruses, such as hepatitis A, B, and E, were reported to affect of various extrahepatic tissues, such as the kidney, thyroid, pancreas, and bone marrow 17 , 18 . The presence of these viruses in pancreatic tissue induces fibrotic or chronic inflammatory changes resulting from the excessive deposition of the extracellular matrix, with the possibility of progression to metaplasia and subsequently, to malignant transformation 19 . Ying Kou also found the higher uptake of 18 F-FAPI in the pancreas, with the SUVmax ± SD of (4.7 ± 1.5) 20 , which is very close to our results (SUVmax 18 F-FAPI: 4.48 ± 0.98).…”

Section: Discussionmentioning

confidence: 99%

Non-specific uptake of 18F-FAPI-04 in the pancreas and its related factors: a post-hoc analysis of an ongoing prospective clinical trial

Li,

Gao,

et al. 2024

Sci Rep

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This study aimed to analyze the characteristics of the non-specific uptake (NSU) of 18F-labeled fibroblast activation protein inhibitor (18F-FAPI) of the pancreas and investigate the related factors. Totally, 78 patients who underwent both 18F-fluorodeoxyglucose (FDG) and 18F-FAPI PET/CT examinations were divided into normal (n = 53) and NSU (n = 25) groups. The differences in general information, medical history, laboratory indexes and uptake were compared. Receiver operating characteristic (ROC) curves were used to analyze the optimal cut-off values. The correlations between 18F-FAPI-SUVmax and blood cell analysis, liver function indexes, tumor markers, and inflammatory indices were analyzed. The logistic regression model was used to estimate the independent factors. Both 18F-FAPI (4.48 ± 0.98 vs. 2.01 ± 0.53, t = 11.718, P < 0.05) and 18F-FDG (2.23 ± 0.42 vs. 2.02 ± 0.44, t = 2.036, P = 0.045) showed significantly higher in NSU group. Patients in the NSU group tended to be complicated with a history of drinking (P = 0.034), chronic liver diseases (P = 0.006), and surgery of gastrectomy (P = 0.004). ROC analysis showed cutoff values of 3.25 and 2.05 for 18F-FAPI and 18F-FDG in identifying the NSU. Patients in the NSU group showed less platelet count, higher platelet volume, higher total bilirubin, direct or indirect bilirubin (P < 0.05). Platelet count, platelet crit, large platelet ratio, aspartate aminotransferase (AST), α-l-fucosidase, and total, direct or indirect bilirubin were correlated with 18F-FAPI-SUVmax (P < 0.05). AST [1.099 (1.014, 1.192), P = 0.021] and total bilirubin [1.137 (1.035, 1.249), P = 0.007] were two independent factors in the step forward logistic regression, and platelet/% [1.079 (1.004, 1.160), P = 0.039] and total bilirubin [1.459 (1.016, 2.095), P = 0.041] were two independent factors in the step backward logistic regression for the prediction of pancreatic uptake of 18F-FAPI. 18F-FAPI-PET/CT was better than 18F-FDG in predicting the pancreatic NSU, and NSU is related to a history of drinking, chronic liver diseases, gastrectomy, heteromorphic platelet, and impaired liver function.

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“…Liver fibrosis is a common clinical pathophysiological process that is almost irreversible using existing methods. Viruses, drug toxicity, alcohol abuse, and a high-fat diet may cause chronic liver damage [ 43 ]. The injured liver maintains functional continuity and structural integrity through the regeneration and reconstruction of parenchymal cells and the formation of nonfunctional fibrous connective tissue by some mesenchymal cells.…”

Section: Ferroptosis and Fibrosismentioning

confidence: 99%

“…The injured liver maintains functional continuity and structural integrity through the regeneration and reconstruction of parenchymal cells and the formation of nonfunctional fibrous connective tissue by some mesenchymal cells. Persistent activation of hepatic stellate cells (HSCs) with a fibroblast phenotype is proposed to be responsible for the distortion and imbalance of normal liver tissue leading to fibrosis [ 43 ]. The occurrence and development of liver fibrosis correlates with pathophysiological processes such as inflammation, iron overload, and oxidative stress [ 44 ] ( Figure 2 ).…”

Section: Ferroptosis and Fibrosismentioning

confidence: 99%

Physiological Effects of Ferroptosis on Organ Fibrosis

Dong²,

et al. 2022

Oxidative Medicine and Cellular Longevity

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Ferroptosis is a new type of programmed cell death with unique morphological, biochemical, and genetic features. From the initial study of histomorphology to the exploration of subcellular organelles and even molecular mechanisms, a net connecting ferroptosis and fibrosis is being woven and formed. Inflammation may be the bridge between both processes. In this review, we will discuss the ferroptosis theory and process and the physiological functions of ferroptosis, followed by a description of the pathological effects and the underlying mechanisms of ferroptosis in the pathogenesis of tumorigenesis, ischemic damage, degenerative lesions, autoimmune diseases, and necroinflammation. We then focus on the role of ferroptosis in the fibrosis process in the liver, lung, kidney, heart, and other organs. Although the molecular mechanism of ferroptosis has been explored extensively in the past few years, many challenges remain to be resolved to translate this information into antifibrotic practice, which is becoming a promising new direction in the field of fibrotic disease prevention and treatment.

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When healing turns into killing – the pathophysiology of pancreatic and hepatic fibrosis

Abstract: support-information-section).

Cited by 12 publications

References 360 publications

Global Transcriptomics of Congenital Hepatic Fibrosis in Autosomal Recessive Polycystic Kidney Disease using PCK rats

Global Transcriptomics of Congenital Hepatic Fibrosis in Autosomal Recessive Polycystic Kidney Disease using PCK rats

Non-specific uptake of 18F-FAPI-04 in the pancreas and its related factors: a post-hoc analysis of an ongoing prospective clinical trial

Physiological Effects of Ferroptosis on Organ Fibrosis

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