Uloga koštanih morfogenetskih proteina i srodnih molekula u procesu eksperimentalno izazvane fibroze jetre u štakora

Grgurević, Ivica (2010) Uloga koštanih morfogenetskih proteina i srodnih molekula u procesu eksperimentalno izazvane fibroze jetre u štakora. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Aims: To analyze the role of bone morphogenetic proteins (BMP) and related molecules ( BMP-1) during liver fibrosis (LF) development and regression and possibility of their therapeutic applicability. Materials and methods: We used exprimental model of CCl4 -induced rat LF. In the prevention arm the animals (8 per group) had recieved BMP-7, BMP1-3Ab or their combination along with CCl4 for 14 weeks. In the therepeutic arm the same therapy had been administrated for 4 weeks to rats with already established cirrhosis following the withdrawal of CCl4. Amount of LF was assessed by hystological, morphometic analysis and hydroxyproline determination. Gene expression analysis was performed by qRT-PCR, and protein expression by immunohystochemistry. Results: Increased Bmp7 and decreased Bmp4 gene expression was detected in cirrhotic liver, while the signifficant increase of Bmp 2&4 and decrease of Bmp1&7 was observed during the recovery phase. Effective prevention of LF development was achieved by the administration of BMP-7 or BMP1-3Ab (15μg/kg), or their combination. Administration of BMP-7 or BMP-7 + BMP1-3Ab (2,5 μg /kg) combination also led to significant regression of LF in previously cirrhotic rats. Conclusion: Bone morphogenetic proteins including BMP-1 have important roles during LF development and regression while BMP-7 and BMP1-3Ab exert antifibrotic effects.

Abstract in Croatian

Ciljevi istraživanja: Proučiti ulogu koštanih morfogenetskih proteina (BMP) i srodnih molekula značajnih za biologiju izvanstaničnog matriksa ( BMP-1) u procesima razvoja i regresije jetrene fibroze, kao i mogućnost njihove terapijske primjene. Materijali i metode: Korišten je model eksperimentalno izazvane fibroze jetre u štakora primjenom CCl4. U prevencijskom dijelu pokusa životinje su (n=8 po skupini) tijekom 14 tjedana uz CCl4 dobivale i BMP-7, BMP1-3Ab ili njihovu kombinaciju, dok je u terapijskom pokusu ista terapija davana 4 tjedna životinjama s već razvijenom cirozom, a nakon prestanka primjene CCl4. Zastupljenost fibroze u jetri analizirana je histološki, morfometrijski i određivanjem koncentracije hidroksiprolina. Za analizu genske ekspresije u jetri korištena je qRT-PCR metoda. Imunohistokemijski je analizirana ekspresija proteina od interesa. Rezultati: U cirozi je povećana ekspresija Bmp7 i smanjenja Bmp4 gena, dok u fazi oporavka značajno raste ekspresija Bmp2 i 4, a smanjuje se ekspresija Bmp1 i 7 gena. Učinkovitost u prevenciji razvoja fibroze pokazuju BMP-7 i BMP1-3Ab (15μg/kg), te njihova kombinacija. Primjena BMP-7 i kombinacije BMP-7 + BMP1-3Ab (2,5 μg/kg) dovodi do značajne regresije fibroze kod životinja s cirozom. Zaključak: Koštani morfogenetski proteini uključujući i BMP-1 igraju značajnu ulogu u procesu razvoja i regresije jetrene fibroze, pri čemu BMP-7 i BMP1-3Ab imaju antifibrozno djelovanje.

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