The therapeutic effect of the neuropeptide hormone somatostatin on Schistosoma mansoni caused liver fibrosis.
BACKGROUND
The neuropeptide somatostatin is one of the major regulatory peptides in the central nervous system and the digestive tract. Our recent work has delineated an association between fibrosis and low levels of endogenous somatostatin plasma levels in Schistosoma mansoni infected subjects. Based on these results this paper explores the therapeutic potential of somatostatin in a mouse model of hepatic fibrosis associated with S. mansoni infections.


METHODS
Groups of outbred Swiss mice were infected with 100 S. mansoni cercariae, infection maintained till weeks 10 or 14, and then somatostatin therapy delivered in two regimens -- either a one or a two-day treatment. All animals were sacrificed one week after therapy and controlled for liver, spleen and total body weight. Circulating somatostatin levels in mice plasma were measured at the time of sacrifice by means of a radio-immuno assay. GraphPad Prism was used for statistical calculations.


RESULTS
Somatostatin administration showed little toxicity, probably due to its short half-life. Total liver and spleen weights of S. mansoni infected animals increased over time, with no changes observed due to somatostatin therapy. Total body weights were decreased after infection but were not affected by somatostatin therapy. Snap frozen liver sections were stained with haematoxylin-eosin or Masson's trichrome to study parasite count, hepatocyte status, granuloma size and cellularity. After somatostatin treatment mean egg counts per liver section (43.76 +/- 3.56) were significantly reduced as compared to the egg counts in untreated mice after 10 weeks of infection (56.01 +/- 3.34) (P = 0.03). Similar significant reduction in parasite egg counts were also observed after somatostatin treatment at 14 weeks of infection (56.62 +/- 3.02) as compared to untreated animals (69.82 +/- 2.77)(P = 0.006). Fibrosis was assessed from the spectrophotometric determination of tissue hydroxyproline. Infection with S. mansoni caused increased hydroxyproline levels (9.37 +/- 0.63 micromol at wk 10; 9.65 +/- 0.96 micromol at wk 14) as compared to uninfected animals (1.06 +/- 0.10 micromol). This significant increase in collagen content (P = 0.01; 0.007 respectively) marks the fibrosis observed at these time points. Treatment with somatostatin resulted in a significant decrease in hydroxyproline levels both at wk 10 (4.76 +/- 0.58 micromol) and at wk 14 (5.8 +/- 1.13 micromol) (P = 0.01; 0.03 respectively). Endogenous somatostatin levels were increased at wk 10 (297 +/- 37.24 pg/ml) and wk 14 (206 +/- 13.30 pg/ml) of infection as compared to uninfected mice (119 +/- 11.99 pg/ml) (P = 0.01; 0.008 respectively). Circulating somatostatin levels in infected animals were not significantly affected by somatostatin treatment. Hepatocyte status remained unaltered and granulomas were not remarkably changed in size or cellularity.


CONCLUSIONS
Our experiments reveal an antifibrotic effect of somatostatin in schistosomiasis. We have previously shown that the somatostatin receptors SSTR2 and SSTR3 are present on the parasite egg and worms. We therefore hypothesize that somatostatin reduces either the number of parasite eggs or the secretion of fibrosis inducing-mediators. Our data suggest somatostatin may have therapeutic potential in S. mansoni mediated liver pathology.
Chatterjee
Shyama
S
Laboratory of Pathology, Faculty of Medicine, University of Antwerp, Universiteitsplein-1, B-2610 Antwerp, Belgium. Shyama.Chatterjee@ua.ac.be
Vrolix
Gunther
G
Depoortere
Inge
I
Peeters
Theo
T
Van Marck
Eric
E
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000209:etiology / Q000469:parasitology*; D008297:Male; D051379:Mice; D009929:Organ Size; D012555:Schistosomiasis mansoni / Q000150:complications*; D013004:Somatostatin / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D013154:Spleen / Q000473:pathology; D013997:Time Factors
D013004:Somatostatin