Hepatocellular carcinoma (HCC) is a major global health problem, which has a grave morbidity and mortality. Over the past few decades, no effective systemic therapeutic modalities have been established for patients with the unresectable HCC in advanced stage. Sorafenib is a small molecule that blocks cancer cell proliferation by targeting the intracellular signaling pathway at the level of Raf-1 and B-Raf serine-threonine kinases, and exerts an anti-angiogenic effect by targeting the vascular endothelial growth factor receptor-1, 2 and 3, and platelet-derived growth factor receptor-beta tyrosine kinases. Recently, two clinical successful applications, SHARP and Asia-Pacific trial, of multikinase inhibitor sorafenib represent a significant advance in the treatment of advanced HCC patients without a curative chance. However, because the results of clinical trials show diverse responses in a subset of HCC patients, a molecular classification of HCC through the excavation of specific biomarkers related to its biological behavior is necessary for sorting HCC patients to each group with a biological homogeneity, ultimately leading to the most suitable individualization of molecular targeted therapy in HCC.
Antineoplastic Agents/therapeutic use ; Benzenesulfonates/therapeutic use ; Carcinoma, Hepatocellular/pathology/secondary/*therapy ; Humans ; Liver Neoplasms/blood supply/pathology/*therapy ; Neovascularization, Pathologic ; Proto-Oncogene Proteins B-raf/antagonists & inhibitors/metabolism ; Proto-Oncogene Proteins c-raf/antagonists & inhibitors/metabolism ; Pyridines/therapeutic use ; Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors/metabolism ; Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors/metabolism ; Signal Transduction

BACKGROUNDMany studies have suggested that angiotensin II (Ang II) and its receptors may be involved in the development of asthma. However, the expression of angiotensin II receptors (AGTR) is not clear in the lung tissue of chronic asthmatics. This study was designed to determine the relationship between airway remodeling, dysfunction and the expression of AGTRs in a rat model of asthma.

METHODSRats were sensitized with ovalbumin (OVA) for 2 weeks. Sixty minutes before an inhalation challenge, the rats were pretreated either with valsartan (15, 30, 50 mg x kg(-1) x d(-1)) or saline intragastrically. Then the rats received an OVA challenge for 30 alternative days. Acetylcholine (Ach)-induced bronchoconstriction was measured after the final antigen challenge. White cell counts in bronchoalveolar lavage fluid (BALF) and morphological changes in the airways were then assessed. The levels of transforming growth factor-beta 1 (TGF-beta(1)) and platelet-derived growth factor (PDGF) in BALF were detected by ELISA. The levels of AGTR1 and AGTR2 mRNA and protein in lung tissues were measured by RT-PCR and Western blotting.

RESULTSAGTR1 mRNA and protein levels in repeatedly OVA-challenged rats were significantly increased as compared with negative controls. The AGTR1 mRNA expression versus white cell counts of BALF and airway wall thickness (mainly in small airways) in lungs of chronic antigen-exposed rats were positively correlated. Valsartan decreased the level of AGTR1 in repeatedly OVA-challenged rats. However, AGTR2 mRNA and protein levels in the OVA-challenged rats and high-dose valsartan-treated rats (50 mg x kg(-1) x d(-1)) were also increased. Valsartan significantly decreased inflammatory cell accumulation and attenuated Ach-evoked bronchoconstriction in repeatedly antigen-challenged rats. Valsartan also decreased allergen-induced structural changes in rat airway (including total airway wall thickness and smooth muscle area) and the levels of TGF-beta(1) and PDGF in BALF.

CONCLUSIONSAGTR1 expression is potentially associated with airway remodeling and dysfunction in asthma. Ang II and AGTR1 may participate in airway inflammation and airway remodeling of chronic antigen-exposed rats. Valsartan, a AGTR1 antagonist, could inhibit AGTR1 expression and partially inhibits structural airway changes as well as airway inflammation in chronic OVA-exposed rats.

Angiotensin II Type 1 Receptor Blockers ; pharmacology ; Angiotensin Receptor Antagonists ; Animals ; Asthma ; chemically induced ; genetics ; metabolism ; Blotting, Western ; Bronchoalveolar Lavage Fluid ; chemistry ; Enzyme-Linked Immunosorbent Assay ; Gene Expression ; drug effects ; Lung ; drug effects ; metabolism ; pathology ; Male ; Ovalbumin ; Platelet-Derived Growth Factor ; metabolism ; Rats ; Rats, Wistar ; Receptor, Angiotensin, Type 1 ; genetics ; metabolism ; Receptor, Angiotensin, Type 2 ; genetics ; metabolism ; Receptors, Angiotensin ; genetics ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Tetrazoles ; pharmacology ; Transforming Growth Factor beta1 ; metabolism ; Valine ; analogs & derivatives ; pharmacology ; Valsartan