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We have reported that von Hippel-Lindau protein (pVHL) expression is elevated in human and mouse fibrotic lungs and that overexpression of pVHL stimulates fibroblast proliferation. We sought to determine whether loss of pVHL in fibroblasts prevents injury and fibrosis in mice that are treated with bleomycin. We generated heterozygous fibroblast-specific pVHL knockdown mice (Fsp-VHL+/-) and homozygous fibroblast-specific pVHL knockout mice (Fsp-VHL-/-) by crossbreeding vhlh 2-lox mice (VHL+/+) with Fsp-Cre mice. Our data show that Fsp-VHL-/- but not Fsp-VHL+/- mice have elevated red blood cell counts, hematocrit, hemoglobin content, and expression of HIF targets, indicating HIF activation. To examine the role of pVHL in bleomycin-induced lung injury and fibrosis in vivo, we administered PBS or bleomycin to age-, sex-, and strain-matched 8-week-old VHLfl/fl, Fsp-VHL+/-, and Fsp-VHL-/- mice. In Fsp-VHL+/- and Fsp-VHL-/- mice, bleomycin-induced collagen accumulation, fibroblast proliferation, differentiation, and matrix protein dysregulation were markedly attenuated. Suppression of pVHL also decreased bleomycin-induced Wnt signaling and PGE2 signaling but did not affect bleomycin-induced initial acute lung injury and lung inflammation. These results indicate that pVHL has a pivotal role in bleomycin-induced pulmonary fibrosis, possibly via a HIF-independent pathway. Paradoxically pVHL does not affect bleomycin-induced lung injury and inflammation, indicating a separation of the mechanisms involved in injury/inflammation from those involved in pulmonary fibrosis.
This article was published in the following journal.
Name: American journal of respiratory cell and molecular biology
To detect VHL gene mutation in a pedigree affected with von Hippel-Lindau syndrome (VHL).
von Hippel-Lindau disease, comprising renal cancer, hemangioblastoma and/or pheochromocytoma (PHEO) is caused by missense or truncating variants of the VHL tumor suppressor gene, which is involved in ...
We reviewed the feasibility and safety of nephron sparing surgery for renal cell carcinoma in patients with von Hippel Lindau (VHL) disease.
Familiar cancers represent a privileged point of view for studying the complex cellular events inducing tumor transformation. Von Hippel-Lindau syndrome, a familiar predisposition to develop cancer is...
Von-Hippel Lindau (VHL) disease is rare neurocutaneous disorder arising from an inactivating mutation of the VHL gene on chromosome 3p35. The disease is inherited in an autosomal dominant fashion and ...
RATIONALE: The identification of gene mutations in individuals who have or are at risk for von Hippel-Lindau syndrome may allow doctors to better determine the genetic processes involved i...
The purpose of this study is to determine whether PTK787/ZK 222584 is effective in treating hemangioblastoma of the brain and/or retina in patients with von Hippel-Lindau disease. The stud...
The purpose of this study is to determine if contrast-enhanced ultrasound can detect abnormal features of kidney lesions in patients with Von-Hippel Lindau with the same accuracy as conven...
This study is designed to investigate PT2977 as a treatment for VHL disease associated RCC.
RATIONALE: Genetic studies may help in understanding the genetic processes involved in the development of some types of cancer. PURPOSE: Genetic study to determine how reproductive, hormo...
A ubiquitin-protein ligase that mediates OXYGEN-dependent polyubiquitination of HYPOXIA-INDUCIBLE FACTOR 1, ALPHA SUBUNIT. It is inactivated in VON HIPPEL-LINDAU SYNDROME.
A complex of related glycopeptide antibiotics from Streptomyces verticillus consisting of bleomycin A2 and B2. It inhibits DNA metabolism and is used as an antineoplastic, especially for solid tumors.
An autosomal dominant disorder caused by mutations in a tumor suppressor gene. This syndrome is characterized by abnormal growth of small blood vessels leading to a host of neoplasms. They include HEMANGIOBLASTOMA in the RETINA; CEREBELLUM; and SPINAL CORD; PHEOCHROMOCYTOMA; pancreatic tumors; and renal cell carcinoma (see CARCINOMA, RENAL CELL). Common clinical signs include HYPERTENSION and neurological dysfunctions.
A benign tumor of the nervous system that may occur sporadically or in association with VON HIPPEL-LINDAU DISEASE. It accounts for approximately 2% of intracranial tumors, arising most frequently in the cerebellar hemispheres and vermis. Histologically, the tumors are composed of multiple capillary and sinusoidal channels lined with endothelial cells and clusters of lipid-laden pseudoxanthoma cells. Usually solitary, these tumors can be multiple and may also occur in the brain stem, spinal cord, retina, and supratentorial compartment. Cerebellar hemangioblastomas usually present in the third decade with INTRACRANIAL HYPERTENSION, and ataxia. (From DeVita et al., Cancer: Principles and Practice of Oncology, 5th ed, pp2071-2)
A Fanconi anemia complementation group protein. It is an essential component of a nuclear core complex that protects the GENOME against CHROMOSOMAL INSTABILITY. It interacts directly with FANCG PROTEIN and helps stabilize a complex with FANCA PROTEIN and FANCC PROTEIN.
Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...
Pulmonary relating to or associated with the lungs eg Asthma, chronic bronchitis, emphysema, COPD, Cystic Fibrosis, Influenza, Lung Cancer, Pneumonia, Pulmonary Arterial Hypertension, Sleep Disorders etc Follow and track Lung Cancer News ...