Lung tissue remodelling in MCT-induced pulmonary hypertension: a proposal for a novel scoring system and changes in extracellular matrix and fibrosis associated gene expression.
Pulmonary hypertension (PH) is associated with vasoconstriction and remodelling. We studied lung tissue remodelling in a rat model of PH with special focus on histology and extracellular matrix (ECM) remodelling. After induction of PH by monocrotaline, lung tissue was analysed histologically, by gene expression analysis and immunofluorescence labelling of ED-A domain containing fibronectin (ED-A+ Fn), B domain containing tenascin-C (B+ Tn-C) as well as alpha-smooth muscle actin (α-SMA). Serum concentrations of ED-A+ Fn were determined by ELISA. Systolic right ventricular pressure (RVPsys) values were significantly elevated in PH (n = 18; 75 ± 26.4 mmHg) compared to controls (n = 10; 29 ± 19.3 mmHg; p = 0.015). The histological sum-score was significantly increased in PH (8.0 ± 2.2) compared to controls (2.5 ± 1.6; p < 0.001). Gene expression analysis revealed relevant induction of several key genes of extracellular matrix remodelling. Increased protein deposition of ED-A+ Fn but not of B+ Tn-C and α-SMA in lung tissue was found in PH (2.88 ± 3.19 area%) compared to controls (1.32 ± 0.16 area%; p = 0.030). Serum levels of ED-A+ Fn were significantly higher in PH (p = 0.007) positively correlating with RVPsys (r = 0.618, p = 0.019). We here present a novel histological scoring system to assess lung tissue remodelling in PH. Gene expression analysis revealed induction of candidate genes involved in collagen matrix turnover, fibrosis and vascular remodelling. The stable increased tissue deposition of ED-A+ Fn in PH as well as its dynamics in serum suggests a role as a promising novel biomarker and potential therapeutic target.
Department of Internal Medicine I, Jena University Hospital, Jena, Germany.
Marcus
M
Franz
Department of Internal Medicine I, Jena University Hospital, Jena, Germany.
Katja
K
Grün
Department of Angiology, Cardiovascular Center Bad Bevensen, Bad Bevensen, Germany.
Stefan
S
Betge
Department of Internal Medicine I, Jena University Hospital, Jena, Germany.
Ilonka
I
Rohm
Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, Jena, Germany.
Bernadin
B
Ndongson-Dongmo
Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, Jena, Germany.
Reinhard
R
Bauer
Department of Internal Medicine I, Jena University Hospital, Jena, Germany.
P Christian
PC
Schulze
Clinic of Internal Medicine II, Department of Cardiology, Paracelsus Medical University of Salzburg, Austria.
Michael
M
Lichtenauer
Institute of Pathology, Jena University Hospital, Jena, Germany.
Iver
I
Petersen
Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Zurich, Switzerland.
Dario
D
Neri
Institute of Pathology, Jena University Hospital, Jena, Germany.
Alexander
A
Berndt
Department of Internal Medicine, Division of Cardiology, Pulmonology and Vascular Medicine, Heinrich-Heine-University, Düsseldorf, Germany.
Christian
C
Jung
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D016686:Monocrotaline; D020411:Oligonucleotide Array Sequence Analysis; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D019063:Tenascin / Q000235:genetics / Q000378:metabolism; D066253:Vascular Remodeling / Q000235:genetics*
D000199:Actins; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D016686:Monocrotaline; D019063:Tenascin; C498862:Acta2 protein, rat
extracellular matrix; fibronectin; histological score; pulmonary hypertension; remodeling