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Article ; Online: The Matrisome, Inflammation, and Liver Disease.

Dolin, Christine E / Arteel, Gavin E

2020 Volume 40, Issue 2, Page(s) 180–188

Abstract: Chronic fatty liver disease is common worldwide. This disease is a spectrum of disease states, ranging from simple steatosis (fat accumulation) to inflammation, and eventually to fibrosis and cirrhosis if untreated. The fibrotic stage of chronic liver ... ...

Abstract	Chronic fatty liver disease is common worldwide. This disease is a spectrum of disease states, ranging from simple steatosis (fat accumulation) to inflammation, and eventually to fibrosis and cirrhosis if untreated. The fibrotic stage of chronic liver disease is primarily characterized by robust accumulation of extracellular matrix (ECM) proteins (collagens) that ultimately impairs the function of the organ. The role of the ECM in early stages of chronic liver disease is less well-understood, but recent research has demonstrated that several changes in the hepatic ECM in prefibrotic liver disease are not only present but may also contribute to disease progression. The purpose of this review is to summarize the established and proposed changes to the hepatic ECM that may contribute to inflammation during earlier stages of disease development, and to discuss potential mechanisms by which these changes may mediate the progression of the disease.
MeSH term(s)	Disease Progression ; Extracellular Matrix Proteins/metabolism ; Humans ; Inflammation/immunology ; Inflammation/metabolism ; Liver Diseases/immunology ; Liver Diseases/metabolism
Chemical Substances	Extracellular Matrix Proteins
Language	English
Publishing date	2020-01-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	603177-8
ISSN	1098-8971 ; 0272-8087
ISSN (online)	1098-8971
ISSN	0272-8087
DOI	10.1055/s-0039-3402516
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Article: The Matrisome, Inflammation, and Liver Disease

Dolin, Christine E. / Arteel, Gavin E.

Seminars in Liver Disease

2020 Volume 40, Issue 02, Page(s) 180–188

Abstract	Chronic fatty liver disease is common worldwide. This disease is a spectrum of disease states, ranging from simple steatosis (fat accumulation) to inflammation, and eventually to fibrosis and cirrhosis if untreated. The fibrotic stage of chronic liver disease is primarily characterized by robust accumulation of extracellular matrix (ECM) proteins (collagens) that ultimately impairs the function of the organ. The role of the ECM in early stages of chronic liver disease is less well-understood, but recent research has demonstrated that several changes in the hepatic ECM in prefibrotic liver disease are not only present but may also contribute to disease progression. The purpose of this review is to summarize the established and proposed changes to the hepatic ECM that may contribute to inflammation during earlier stages of disease development, and to discuss potential mechanisms by which these changes may mediate the progression of the disease.
Keywords	liver disease ; hepatic ; acute phase
Language	English
Publishing date	2020-01-07
Publisher	Thieme Medical Publishers
Publishing place	Stuttgart ; New York
Document type	Article
ZDB-ID	603177-8
ISSN	1098-8971 ; 0272-8087
ISSN (online)	1098-8971
ISSN	0272-8087
DOI	10.1055/s-0039-3402516
Database	Thieme publisher's database

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Article ; Online: Organ-Organ Crosstalk and Alcoholic Liver Disease.

Poole, Lauren G / Dolin, Christine E / Arteel, Gavin E

Biomolecules

2017 Volume 7, Issue 3

Abstract: Alcohol consumption is a common custom worldwide, and the toxic effects of alcohol on several target organs are well-understood. Given the poor prognosis of treating clinically-relevant alcoholic liver disease (ALD) (i.e., alcoholic hepatitis (AH) and ... ...

Abstract	Alcohol consumption is a common custom worldwide, and the toxic effects of alcohol on several target organs are well-understood. Given the poor prognosis of treating clinically-relevant alcoholic liver disease (ALD) (i.e., alcoholic hepatitis (AH) and cirrhosis), additional research is required to develop more effective therapies. While the stages of ALD have been well-characterized, targeted therapies to prevent or reverse this process in humans are still needed. Better understanding of risk factors and mechanisms underlying disease progression can lead to the development of rational therapies to prevent or reverse ALD in the clinic. A potential area of targeted therapy for ALD may be organ-organ communication in the early stages of the disease. In contrast to AH and end-stage liver diseases, the involvement of multiple organs in the development of ALD is less understood. The impact of these changes on pathology to the liver and other organs may not only influence disease progression during the development of the disease, but also outcomes of end stages diseases. The purpose of this review is to summarize the established and proposed communication between the liver and other organ systems that may contribute to the development and progression of liver disease, as well as to other organs. Potential mechanisms of this organ-organ communication are also discussed.
MeSH term(s)	Biomarkers, Tumor/metabolism ; Cell Communication/drug effects ; Cytokines/metabolism ; Disease Progression ; Extracellular Vesicles/metabolism ; Humans ; Liver Diseases, Alcoholic/drug therapy ; Liver Diseases, Alcoholic/metabolism ; Liver Diseases, Alcoholic/pathology ; Risk Factors
Chemical Substances	Biomarkers, Tumor ; Cytokines
Language	English
Publishing date	2017-08-16
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom7030062
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: A plasma peptidomic signature reveals extracellular matrix remodeling and predicts prognosis in alcohol-related hepatitis.

Sayed, Khaled / Dolin, Christine E / Wilkey, Daniel W / Li, Jiang / Sato, Toshifumi / Beier, Juliane I / Argemi, Josepmaria / Bataller, Ramon / Wahed, Abdus S / Merchant, Michael L / Benos, Panayiotis V / Arteel, Gavin E

medRxiv : the preprint server for health sciences

2023

Abstract: Alcohol-related hepatitis (AH) is plagued with high mortality and difficulty in identifying at-risk patients. The extracellular matrix undergoes significant remodeling during inflammatory liver injury that can be detected in biological fluids and ... ...

Abstract	Alcohol-related hepatitis (AH) is plagued with high mortality and difficulty in identifying at-risk patients. The extracellular matrix undergoes significant remodeling during inflammatory liver injury that can be detected in biological fluids and potentially used for mortality prediction. EDTA plasma samples were collected from AH patients (n= 62); Model for End-Stage Liver Disease (MELD) score defined AH severity as moderate (12-20; n=28) and severe (>20; n=34). The peptidome data was collected by high resolution, high mass accuracy UPLC-MS. Univariate and multivariate analyses identified differentially abundant peptides, which were used for Gene Ontology, parent protein matrisomal composition and protease involvement. Machine learning methods were used on patient-specific peptidome and clinical data to develop mortality predictors. Analysis of plasma peptides from AH patients and healthy controls identified over 1,600 significant peptide features corresponding to 130 proteins. These were enriched for ECM fragments in AH samples, likely related to turnover of hepatic-derived proteins. Analysis of moderate versus severe AH peptidomes showed a shift in abundance of peptides from collagen 1A1 and fibrinogen A proteins. The dominant proteases for the AH peptidome spectrum appear to be CAPN1 and MMP12. Increase in hepatic expression of these proteases was orthogonally-validated in RNA-seq data of livers from AH patients. Causal graphical modeling identified four peptides directly linked to 90-day mortality in >90% of the learned graphs. These peptides improved the accuracy of mortality prediction over MELD score and were used to create a clinically applicable mortality prediction assay. A signature based on plasma peptidome is a novel, non-invasive method for prognosis stratification in AH patients. Our results could also lead to new mechanistic and/or surrogate biomarkers to identify new AH mechanisms. Lay summary: We used degraded proteins found the blood of alcohol-related hepatitis patients to identify new potential mechanisms of injury and to predict 90 day mortality.
Language	English
Publishing date	2023-12-14
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.12.13.23299905
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Article ; Online: Fibrosis resolution in the mouse liver: Role of Mmp12 and potential role of calpain 1/2.

Sato, Toshifumi / Head, Kimberly Z / Li, Jiang / Dolin, Christine E / Wilkey, Daniel / Skirtich, Nolan / Smith, Katelyn / McCreary, Dylan D / Liu, Sylvia / Beier, Juliane I / Singhi, Aatur D / McEnaney, Ryan M / Merchant, Michael L / Arteel, Gavin E

Matrix biology plus

2022 Volume 17, Page(s) 100127

Abstract: Although most work has focused on resolution of collagen ECM, fibrosis resolution involves changes to several ECM proteins. The purpose of the current study was twofold: 1) to examine the role of MMP12 and elastin; and 2) to investigate the changes in ... ...

Abstract	Although most work has focused on resolution of collagen ECM, fibrosis resolution involves changes to several ECM proteins. The purpose of the current study was twofold: 1) to examine the role of MMP12 and elastin; and 2) to investigate the changes in degraded proteins in plasma (i.e., the "degradome") in a preclinical model of fibrosis resolution. Fibrosis was induced by 4 weeks carbon tetrachloride (CCl
Language	English
Publishing date	2022-12-28
Publishing country	Netherlands
Document type	Journal Article
ISSN	2590-0285
ISSN (online)	2590-0285
DOI	10.1016/j.mbplus.2022.100127
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Article ; Online: Modeling the Kinetics of Integrin Receptor Binding to Hepatic Extracellular Matrix Proteins.

Hudson, Shanice V / Dolin, Christine E / Poole, Lauren G / Massey, Veronica L / Wilkey, Daniel / Beier, Juliane I / Merchant, Michael L / Frieboes, Hermann B / Arteel, Gavin E

Scientific reports

2017 Volume 7, Issue 1, Page(s) 12444

Abstract: The composition of the extracellular matrix (ECM) proteins and the expression of their cognate receptors dictate cell behavior and dynamics. In particular, the interactions of ECM proteins with integrin receptors are key mediators of these cellular ... ...

Abstract	The composition of the extracellular matrix (ECM) proteins and the expression of their cognate receptors dictate cell behavior and dynamics. In particular, the interactions of ECM proteins with integrin receptors are key mediators of these cellular processes, playing a crucial role in the progression of several diseases of the liver, including inflammation, fibrosis/cirrhosis and cancer. This study establishes a modeling approach combining computation and experiments to evaluate the kinetics of integrin receptor binding to hepatic ECM proteins. ECM ligand concentration was derived from LC-MS/MS quantification of the hepatic ECM from mice exposed to chronic carbon tetrachloride (CCl
MeSH term(s)	Animals ; Carbon Tetrachloride/toxicity ; Chemical and Drug Induced Liver Injury/genetics ; Chemical and Drug Induced Liver Injury/metabolism ; Chemical and Drug Induced Liver Injury/pathology ; Chromatography, Liquid ; Computer Simulation ; Extracellular Matrix Proteins/classification ; Extracellular Matrix Proteins/genetics ; Extracellular Matrix Proteins/metabolism ; Gene Expression ; Injections, Intraperitoneal ; Integrins/classification ; Integrins/genetics ; Integrins/metabolism ; Kinetics ; Ligands ; Liver/drug effects ; Liver/metabolism ; Liver/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Models, Statistical ; Protein Aggregates ; Protein Binding ; Signal Transduction ; Tandem Mass Spectrometry
Chemical Substances	Extracellular Matrix Proteins ; Integrins ; Ligands ; Protein Aggregates ; Carbon Tetrachloride (CL2T97X0V0)
Language	English
Publishing date	2017-09-29
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-017-12691-y
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Article ; Online: The hepatic "matrisome" responds dynamically to injury: Characterization of transitional changes to the extracellular matrix in mice.

Massey, Veronica L / Dolin, Christine E / Poole, Lauren G / Hudson, Shanice V / Siow, Deanna L / Brock, Guy N / Merchant, Michael L / Wilkey, Daniel W / Arteel, Gavin E

Hepatology (Baltimore, Md.)

2017 Volume 65, Issue 3, Page(s) 969–982

Abstract: The extracellular matrix (ECM) consists of diverse components that work bidirectionally with surrounding cells to create a responsive microenvironment. In some contexts (e.g., hepatic fibrosis), changes to the ECM are well recognized and understood. ... ...

Abstract	The extracellular matrix (ECM) consists of diverse components that work bidirectionally with surrounding cells to create a responsive microenvironment. In some contexts (e.g., hepatic fibrosis), changes to the ECM are well recognized and understood. However, it is becoming increasingly accepted that the hepatic ECM proteome (i.e., matrisome) responds dynamically to stress well before fibrosis. The term "transitional tissue remodeling" describes qualitative and quantitative ECM changes in response to injury that do not alter the overall architecture of the organ; these changes in ECM may contribute to early disease initiation and/or progression. The nature and magnitude of these changes to the ECM in liver injury are poorly understood. The goals of this work were to validate analysis of the ECM proteome and compare the impact of 6 weeks of ethanol diet and/or acute lipopolysaccharide (LPS). Liver sections were processed in a series of increasingly rigorous extraction buffers to separate proteins by solubility. Extracted proteins were identified using liquid chromatography/tandem mass spectrometry (LC-MS/MS). Both ethanol and LPS dramatically increased the number of matrisome proteins ∼25%. The enhancement of LPS-induced liver damage by ethanol preexposure was associated with unique protein changes. Conclusion: An extraction method to enrich the hepatic ECM was characterized. The results demonstrate that the hepatic matrisome responds dynamically to both acute (LPS) and chronic (ethanol) stresses, long before more-dramatic fibrotic changes to the liver occur. The changes to the mastrisome may contribute, at least in part, to the pathological responses to these stresses. It is also interesting that several ECM proteins responded similarly to both stresses, suggesting a common mechanism in both models. Nevertheless, there were responses that were unique to the individual and combined exposures. (Hepatology 2017;65:969-982).
MeSH term(s)	Animals ; Disease Models, Animal ; Disease Progression ; Ethanol/pharmacology ; Extracellular Matrix/drug effects ; Extracellular Matrix/metabolism ; Extracellular Matrix/pathology ; Extracellular Matrix Proteins/drug effects ; Extracellular Matrix Proteins/metabolism ; Lipopolysaccharides/pharmacology ; Liver Cirrhosis/genetics ; Liver Cirrhosis/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Oxidative Stress ; Proteome/genetics ; Random Allocation ; Risk Factors ; Sensitivity and Specificity
Chemical Substances	Extracellular Matrix Proteins ; Lipopolysaccharides ; Proteome ; Ethanol (3K9958V90M)
Language	English
Publishing date	2017-03
Publishing country	United States
Document type	Comparative Study ; Journal Article
ZDB-ID	604603-4
ISSN	1527-3350 ; 0270-9139
ISSN (online)	1527-3350
ISSN	0270-9139
DOI	10.1002/hep.28918
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Article ; Online: Chronic + binge alcohol exposure promotes inflammation and alters airway mechanics in the lung.

Poole, Lauren G / Beier, Juliane I / Torres-Gonzales, Edilson / Schlueter, Connie F / Hudson, Shanice V / Artis, Amanda / Warner, Nikole L / Nguyen-Ho, Calvin T / Dolin, Christine E / Ritzenthaler, Jeffrey D / Hoyle, Gary W / Roman, Jesse / Arteel, Gavin E

Alcohol (Fayetteville, N.Y.)

2018 Volume 80, Page(s) 53–63

Abstract: Introduction: Alcohol use disorders are major risk factors for the development of and susceptibility to acute respiratory distress syndrome. Although these risks of alcohol consumption on the lung are well described, mechanisms by which alcohol abuse ... ...

Abstract	Introduction: Alcohol use disorders are major risk factors for the development of and susceptibility to acute respiratory distress syndrome. Although these risks of alcohol consumption on the lung are well described, mechanisms by which alcohol abuse promotes acute lung injury are poorly understood. These gaps in our understanding are due, at least in part, to limitations of animal models to recapitulate human alcohol consumption. Recently, a new model of chronic plus binge alcohol exposure was developed that is hypothesized to better model drinking patterns of individuals with alcohol use disorders. Specifically, this paradigm models chronic consumption coupled with periodic bouts of heavy drinking. The impacts of this alcohol-exposure regimen on the lung are uncharacterized. Therefore, the goal of this study was to examine lung injury and inflammation in a well-characterized experimental model of chronic + binge alcohol exposure. Methods: 10-week-old male C57Bl6/J mice were administered ethanol-containing (or isocaloric control) liquid diet for 10 days, followed by a single ethanol gavage (5 g/kg). Lung inflammation and pulmonary function were assessed. Results: Ten days of ethanol-containing liquid diet alone (chronic) did not detectably affect any variables measured. However, ethanol diet plus gavage (chronic + binge) caused neutrophils to accumulate in the lung tissue and in the bronchoalveolar lavage fluid 24 h post-binge. This inflammatory cell recruitment was associated with airway hyper-responsiveness to inhaled methacholine, as indicated by elevated resistance, Newtonian resistance, and respiratory resistance. Conclusions: Taken together, the novel findings reveal that ethanol alone, absent of any secondary inflammatory insult, is sufficient to produce inflammation in the lung. Although these changes were relatively mild, they were associated with functional changes in the central airways. This animal model may be useful in the future for identifying mechanisms by which alcohol abuse sensitizes at-risk individuals to lung injury.
MeSH term(s)	Alcoholism/complications ; Alcoholism/pathology ; Alcoholism/physiopathology ; Animals ; Binge Drinking/complications ; Binge Drinking/pathology ; Binge Drinking/physiopathology ; Disease Models, Animal ; Lung/drug effects ; Lung/pathology ; Lung/physiopathology ; Male ; Mice ; Mice, Inbred C57BL ; Pneumonia/chemically induced ; Pneumonia/pathology ; Pneumonia/physiopathology ; Reverse Transcriptase Polymerase Chain Reaction
Language	English
Publishing date	2018-11-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	605912-0
ISSN	1873-6823 ; 0741-8329
ISSN (online)	1873-6823
ISSN	0741-8329
DOI	10.1016/j.alcohol.2018.10.008
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