ABSTRACT
Myoendothelial junctions are specialised projections of cell : cell contact through the internal elastic lamina between endothelial cells and vascular smooth muscle cells. These junctions allow for endothelial cells and vascular smooth muscle cells to make direct membrane apposition and are involved in cell : cell communication. In this study, we evaluated for the presence of myoendothelial junctions in murine corporal tissue and used plasminogen activator inhibitor (PAI)-1-deficient mice, which lack myoendothelial junctions, to determine whether myoendothelial junctions affect erectile function. Transmission electron microscopy demonstrated the presence of myoendothelial junctions in the corporal tissue of wild-type mice and confirmed the decreased junction numbers in the tissue of PAI-1(-/-) mice. A potential role for myoendothelial junctions in tumescence was established; in that, PAI-1(-/-) mice demonstrated a significantly longer time to achieve maximal intracavernous pressure. Treatment of PAI-1(-/-) mice with recombinant PAI-1 restored the number of myoendothelial junctions in the corporal tissue and also induced a significant decrease in time to maximal corporal pressures. Myoendothelial junctions were similarly identified in the human corporal tissue. These results suggest a critical role for myoendothelial junctions in erectile pathophysiology and therapies aimed at restoring myoendothelial junction numbers in the corporal tissue may provide a novel therapy for erectile dysfunction.
Subject(s)
Endothelium, Vascular/drug effects , Erectile Dysfunction/drug therapy , Intercellular Junctions/drug effects , Muscle, Smooth, Vascular/drug effects , Penile Erection/drug effects , Serpin E2/deficiency , Animals , Cell Communication , Endothelium, Vascular/physiology , Endothelium, Vascular/ultrastructure , Erectile Dysfunction/etiology , Intercellular Junctions/physiology , Intercellular Junctions/ultrastructure , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Electron, Transmission , Muscle, Smooth, Vascular/physiology , Muscle, Smooth, Vascular/ultrastructure , Recombinant Proteins , Serpin E2/therapeutic useABSTRACT
AIM: To compare prospective, long-term quality of life in patients randomised to external beam radiotherapy (EBRT) alone or with a boost of high dose rate (HDR) brachytherapy. MATERIALS AND METHODS: In total, 216 patients participating in the UK randomised trial of EBRT ± HDR brachytherapy were included in this analysis. EBRT delivering 55 Gy in 20 fractions was compared with EBRT followed by HDR brachytherapy of 2 × 8.5 Gy. Quality of life was assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and FACT-G (General) questionnaires, administered before radiotherapy, at 6 months and bi-annually thereafter. Differences in mean FACT global scores and erectile function between treatment arms were compared using chi-squared tests. RESULTS: Over a 10.5 year follow-up, no difference in FACT-G, FACT-P or Trial Outcome Index (TOI) scores was seen between treatments and means were similar to their pretreatment values. Mean erectile function scores in arm 2 were similar to arm 1, but were significantly lower than the pretreatment mean (P ≤ 0.002). There was no evidence that quality of life deteriorated with increasing follow-up time in any of the four FACT domains. CONCLUSIONS: The improved biochemical control of disease seen in these patients with EBRT + HDR brachytherapy coupled with equitoxic early and late urinary and bowel morbidity, indicate a therapeutic advantage, which has now been confirmed by the results for general and prostate-related quality of life changes, despite a decline in erectile function.
Subject(s)
Brachytherapy/methods , Prostatic Neoplasms/radiotherapy , Aged , Aged, 80 and over , Humans , Longitudinal Studies , Male , Middle Aged , Neoplasm Metastasis , Palliative Care , Prospective Studies , Prostatic Neoplasms/pathology , Quality of Life , Salvage Therapy , Treatment OutcomeABSTRACT
A number of serine proteases, matrix metalloproteases, and cysteine proteases were evaluated for their ability to cleave and inactivate the antiprotease, secretory leucoprotease inhibitor (SLPI). None of the serine proteases or the matrix metalloproteases examined cleaved the SLPI protein. However, incubation with cathepsins B, L, and S resulted in the cleavage and inactivation of SLPI. All three cathepsins initially cleaved SLPI between residues Thr(67) and Tyr(68). The proteolytic cleavage of SLPI by all three cathepsins resulted in the loss of the active site of SLPI and the inactivation of SLPI anti-neutrophil elastase capacity. Cleavage and inactivation were catalytic with respect to the cathepsins, so that the majority of a 400-fold excess of SLPI was inactivated within 15 min by cathepsins L and S. Analysis of epithelial lining fluid samples from individuals with emphysema indicated the presence of cleaved SLPI in these samples whereas only intact SLPI was observed in control epithelial lining fluid samples. Active cathepsin L was shown to be present in emphysema epithelial lining fluid and inhibition of this protease prevented the cleavage of recombinant SLPI added to emphysema epithelial lining fluid. Taken together with previous data that demonstrates that cathepsin L inactivates alpha(1)-antitrypsin, these findings indicate the involvement of cathepsins in the diminution of the lung antiprotease screen possibly leading to lung destruction in emphysema.
