Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019214 (hepatosplenomegaly)
 4,408 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acid sphingomyelinase deficiency is a lysosomal storage disorder in which the defective lysosomal hydrolase fails to degrade sphingomyelin. The resulting accumulation of substrate in the lysosomes of histiocytic cells leads to hepatosplenomegaly and severe pulmonary inflammation. Administration of a recombinant AAV1 vector encoding human acid sphingomyelinase to acid sphingomyelinase knockout (ASMKO) mice effectively reduced the accumulated substrate in all of the affected visceral organs. However, more complete and rapid clearance of sphingomyelin was observed when an AAV8-based serotype vector was used in lieu of AAV1. Importantly, AAV8-mediated hepatic expression of higher and sustained levels of the enzyme also corrected the abnormal cellularity, cell differentials, and levels of the chemokine MIP-1alpha in the bronchoalveolar lavage fluids of the ASMKO mice. Treatment also reversed the morphological aberrations associated with the alveolar macrophages of ASMKO mice and restored their phagocytic activity. No antibodies to the expressed enzyme were detected when the viral vectors were used in conjunction with a transcription cassette harboring a liver-restricted enhancer/promoter. Together, these data support the continued development of AAV8-mediated hepatic gene transfer as an approach to treat the visceral manifestations observed in individuals with acid sphingomyelinase deficiency.
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PMID:AAV8-mediated hepatic expression of acid sphingomyelinase corrects the metabolic defect in the visceral organs of a mouse model of Niemann-Pick disease. 1609 9

NK cell-type lymphoproliferative disease of granular lymphocytes can be subdivided into aggressive NK-cell leukemia (ANKL) and chronic NK-cell lymphocytosis (CNKL). Hepatosplenomegaly is observed in ANKL patients, and hepatic failure is a common cause of death. Significant numbers of ANKL cells were pathologically observed in sinusoidal and interlobular regions of the liver, and in the splenic red pulp. In our previous study, ANKL cells were simultaneously positive for CXCR1 and CCR5. So, in order to elucidate the mechanism in the systemic migration of ANKL cells, we investigated the expression of the corresponding chemokines in ANKL compared with CNKL. The serum level of IL-8, MIP-1alpha and MIP-1beta was significantly elevated in ANKL patients, and ANKL cells were highly positive for IL-8, RANTES, MIP-1alpha and MIP-1beta according to intracellular staining and RT-PCR. These chemokines were also positively stained in hepatocytes. The interaction between Fas and Fas ligand (FasL) is supposed to be one of the mechanisms for liver dysfunction in ANKL. The serum concentration of soluble FasL was significantly high in ANKL patients, and ANKL cells expressed FasL protein in the cytoplasm. These results suggest that the chemokine system plays an important role in the transmigration of FasL-expressing ANKL cells.
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PMID:Chemokine system and tissue infiltration in aggressive NK-cell leukemia. 1712 4

Pancytopenia, hepatosplenomegaly and skeletal complications are hallmarks of Gaucher disease. Monitoring of the outcome of therapy on skeletal status of Gaucher patients is problematic since currently available imaging techniques are expensive and not widely accessible. The availability of a blood test that relates to skeletal manifestations would be very valuable. We here report that macrophage inflammatory protein (MIP)-1alpha and MIP-1beta, both implicated in skeletal complications in multiple myeloma (MM), are significantly elevated in plasma of Gaucher patients. Plasma MIP-1alpha of patients (median 78 pg/ml, range 21-550 pg/ml, n=48) is elevated (normal median 9 pg/ml, range 0-208 pg/ml, n=39). Plasma MIP-1beta of patients (median 201 pg/ml, range 59-647 pg/ml, n=49) is even more pronouncedly increased (normal median 17 pg/ml, range 1-41 pg/ml, n=39; one outlier: 122 pg/ml). The increase in plasma MIP-1beta levels of Gaucher patients is associated with skeletal disease. The plasma levels of both chemokines decrease upon effective therapy. Lack of reduction of plasma MIP-1beta below 85 pg/ml during 5 years of therapy was observed in patients with ongoing skeletal disease. In conclusion, MIP-1alpha and MIP-1beta are elevated in plasma of Gaucher patients and remaining high levels of MIP-1beta during therapy seem associated with ongoing skeletal disease.
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PMID:Increased plasma macrophage inflammatory protein (MIP)-1alpha and MIP-1beta levels in type 1 Gaucher disease. 1749 84