Fibrosis-related gene expression in the prostate is modulated by doxazosin treatment

Delella, Flávia Karina; Lacorte, Lívia M.; Almeida, Fernanda Losi Alves de; Pai, Maeli Dal; Felisbino, Sérgio Luís

doi:10.1016/j.lfs.2012.09.017

Cited by 12 publications

(8 citation statements)

References 41 publications

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“…59 Conversely, other studies have shown that the ventral prostates of adult Wistar rats treated with the α-adrenergic receptor antagonist doxazosin contain increased levels of collagen and collagen fibrils compared with untreated controls. 60 A-adrenergic receptor antagonists are known to target vascular and smooth muscle cells in the lower urinary tract. However, myofibroblasts, like smooth muscle cells, are contractile, 55 and further work is required to determine whether myofibroblasts respond to α-adrenergic receptor antagonists in a similar manner to smooth muscle cells in the lower urinary tract.…”

Section: Therapeutic Targeting Of Fibrosismentioning

confidence: 99%

Prostatic fibrosis, lower urinary tract symptoms, and BPH

2013

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Lower urinary tract symptoms (LUTS)—constituting a spectrum disorder that encompasses weak stream, nocturia, and sensations of incomplete emptying and intermittent or hesitant urination—are indicative of lower urinary tract dysfunction (LUTD). LUTD is a progressive disease that can lead to bladder dysfunction if left untreated or treated ineffectively. Sequelae include urinary retention, recurrent UTI, bladder calculi, and, eventually, renal impairment. LUTD involving the prostate is associated with both ageing and inflammation. Tissue inflammation resulting from ageing, infection, or other inflammatory disease processes (for example, type 2 diabetes mellitus) is epidemiologically associated with the subsequent development of tissue fibrosis in multiple organ systems, including the prostate. Recent studies show that tissue fibrosis in the lower urinary tract is associated with LUTD, and suggest that fibrosis might be a previously unrecognized pathobiology that contributes to LUTD. Thus, antifibrotic therapeutic agents should be considered as a new approach to efficaciously treating men with LUTD, especially those who don’t experience durable responses to 5α-reductase inhibitors or α-adrenergic receptor antagonists.

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Section: Therapeutic Targeting Of Fibrosismentioning

confidence: 99%

Prostatic fibrosis, lower urinary tract symptoms, and BPH

2013

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“…Treatment with 5ARIs only reduces glandular tissue whereas the relative abundance of stromal and epithelial cells in BPH nodules is diverse suggesting that this treatment may become less efficient in cases with stromal dominance 12 . Furthermore, both 5ARI and a-B stimulate the TGFβ profibrotic pathway and thus may promote fibrosis 13,14 . In agreement with this, the MTOPS (Medical Therapy of Prostatic Symptoms) study revealed that fibrosis in the transition zone of the prostate is associated with increased risk of clinical progression of LUTS in patients who received combined a-B and 5ARI treatement 15 .…”

Section: Introductionmentioning

confidence: 99%

Prostatic osteopontin expression is associated with symptomatic benign prostatic hyperplasia

Popovics

Awadallah

Kohrt

et al. 2019

Preprint

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AbstractBackgroundMale lower urinary tract symptoms (LUTS) occur in more than half of men above 50 years of age. LUTS were traditionally attributed to benign prostatic hyperplasia (BPH) and therefore the clinical terminology often use LUTS and BPH interchangeably. More recently, LUTS were also linked to fibrogenic and inflammatory processes. We tested whether osteopontin (OPN), a pro-inflammatory and pro-fibrotic molecule, is increased in symptomatic BPH. We also tested whether prostate epithelial and stromal cells secrete OPN in response to pro-inflammatory stimuli and identified downstream targets of OPN in prostate stromal cells.MethodsImmunohistochemistry was performed on prostate sections obtained from the transition zone (TZ) of patients who underwent surgery (Holmium laser enucleation of the prostate) to relieve LUTS i.e. surgical BPH (S-BPH) or patients who underwent radical prostatectomy to remove low-grade prostate cancer (incidental BPH, I-BPH). Images of stained tissue sections were captured with a Nuance Multispectral Imaging system and histoscore, as a measure of OPN staining intensity, was determined with inForm software. OPN protein abundance was determined by Western blot. The ability of prostate cells to secrete osteopontin in response to IL-1β and TGF-β1 was determined in stromal (BHPrS-1) and epithelial (NHPrE-1 and BHPrE-1) cells by ELISA. qPCR was used to measure gene expression changes in these cells in response to OPN.ResultsOPN immunostaining (p=0.0107) and protein levels were more abundant in S-BPH than I-BPH. Staining was distributed across all cell types with highest levels in epithelial cells. Multiple OPN protein variants were identified in immortalized prostate stromal and epithelial cells. TGF-β1 stimulated OPN secretion by NHPrE-1 cells and both IL-1β and TGF-β1 stimulated OPN secretion by BHPrS-1 cells. Interestingly, recombinant OPN increased the mRNA expression of CXCL1, CXCL2, CXCL8, PTGS2 and IL6 in BHPrS-1, but not in epithelial cell lines.ConclusionsOPN is more abundant in prostates of men with S-BPH compared to men with I-BPH. OPN secretion is stimulated by pro-inflammatory cytokines, and OPN acts directly on stromal cells to drive the synthesis of pro-inflammatory mRNAs. Pharmacological manipulation of prostatic OPN may have the potential to reduce LUTS by inhibiting both inflammatory and fibrotic pathways.

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“…Upregulation of COL3A1 is frequently correlated with the fibrotic phenotype of the prostate and an active TGF-β1 signaling pathway [ 9 , 10 , 11 ]. Moreover, downregulation of COL3A1, using anti-fibrotic agents, has been correlated with the attenuation of the fibrotic phenotype in different organs [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. Therefore, COL3A1 could potentially serve as marker for the fibrotic phenotype in the tissues and organs of the pelvis exposed to radiation.…”

Section: Introductionmentioning

confidence: 99%

The SOD Mimic, MnTE-2-PyP, Protects from Chronic Fibrosis and Inflammation in Irradiated Normal Pelvic Tissues

et al. 2017

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Pelvic radiation for cancer therapy can damage a variety of normal tissues. In this study, we demonstrate that radiation causes acute changes to pelvic fibroblasts such as the transformation to myofibroblasts and the induction of senescence, which persist months after radiation. The addition of the manganese porphyrin, MnTE-2-PyP, resulted in protection of these acute changes in fibroblasts and this protection persisted months following radiation exposure. Specifically, at two months post-radiation, MnTE-2-PyP inhibited the number of α-smooth muscle actin positive fibroblasts induced by radiation and at six months post-radiation, MnTE-2-PyP significantly reduced collagen deposition (fibrosis) in the skin and bladder tissues of irradiated mice. Radiation also resulted in changes to T cells. At two months post-radiation, there was a reduction of Th1-producing splenocytes, which resulted in reduced Th1:Th2 ratios. MnTE-2-PyP maintained Th1:Th2 ratios similar to unirradiated mice. At six months post-radiation, increased T cells were observed in the adipose tissues. MnTE-2-PyP treatment inhibited this increase. Thus, MnTE-2-PyP treatment maintains normal fibroblast function and T cell immunity months after radiation exposure. We believe that one of the reasons MnTE-2-PyP is a potent radioprotector is due to its protection of multiple cell types from radiation damage.

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Fibrosis-related gene expression in the prostate is modulated by doxazosin treatment

Cited by 12 publications

References 41 publications

Prostatic fibrosis, lower urinary tract symptoms, and BPH

Prostatic fibrosis, lower urinary tract symptoms, and BPH

Prostatic osteopontin expression is associated with symptomatic benign prostatic hyperplasia

The SOD Mimic, MnTE-2-PyP, Protects from Chronic Fibrosis and Inflammation in Irradiated Normal Pelvic Tissues

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