[Functional morphology of the bladder and its vascular system in relation to age changes and evolution of BPH].

INTRODUCTION: The increase in the proportion of people with various urinary disorders, which are based on anatomical and functional bladder remodeling due to aging, is currently un-deniable. This problem becomes more relevant due to the elevation in life expectancy. At the same time, the features of bladder remodeling, in particular, the structural changes of its vascular bed, are still practically not described in the literature. In men, the lower urinary tract undergoes additional transformation associated with age due to bladder outlet obstruction caused by benign prostatic hyperplasia (BPH). Despite the long history of studying BPH, the morphological basics of its evolution have not yet been fully elucidated, including the development of lower urinary tract decompensation and, in particular, the role of vascular changes. In addition, structural re-modeling of the bladder muscles in BPH is formed in those with pre-existing age-related changes in both the detrusor and its vascular system, which cannot but influence the dynamics of disease progression. AIM: To study the structural changes of detrusor and its vascular bed associated with age, and to establish the role of their patterns in patients with BPH. MATERIALS AND METHODS: The material was a specimen of the bladder wall obtained dur-ing: a) autopsies of 35 men aged 60-80 years who died from diseases not related to urological or cardiovascular pathology; b) autopsies of 35 men aged 60-80 years who had BPH without blad-der decompensation; c) intraoperative biopsies of 25 men of the same age who undergone surgi-cal treatment for chronic urinary retention (postvoid residual volume of more than 300 ml), bilat-eral hydronephrosis, as complications of BPH. As a control, we used the specimens obtained from 20 males aged 20-30 years who died as a result of violence. Histological sections of the bladder wall were stained with hematoxylin-eosin, according to Mason and Hart. Standard microscopy and stereometry of detrusor structural components and morphometry of the urinary bladder vessels were performed using a special ocular insert with 100 equidistant points. During morphometric examination of the vascular bed the thickness of the middle layer of arteries wall (tunica media) was measured, as well as a thickness of the entire wall of the veins in microns. In addition, a Schiff test and Immunohistochemistry (IHC) of these histological sections were performed. The IHC was evaluated using a semi-quantitative method, taking into account the degree of staining in 10 fields of vision (200). The digital material was processed with the STATISTICA program using the Student's t-test. The distribution of the obtained data corresponded to normal. The data were considered re-liable if the probability of making error did not exceed 5% (p<0.05). RESULTS AND DISCUSSION: In the course of natural aging, a structural remodeling of bladder vascular bed was observed, from the development of atherosclerosis of extra-organ arteries to restructuring of intra-organ arteries due to arterial hypertension. The progression of angiopathy leads to the development of chronic detrusor ischemia, which initiates the formation of focal at-rophy of the smooth muscles, destructive changes in the elastic fibers, neurodegeneration and stroma sclerosis. A long-term BPH leads to compensatory detrusor remodeling with hypertrophy of previously unchanged areas. At the same time, age-related atrophic and sclerotic changes in smooth muscles are accompanied with hypertrophy of individual areas of the bladder detrusor. To maintain adequate blood supply to hypertrophied detrusor areas in the arterial and venous bladder vessels, a complex of myogenic structures is formed that can regulate blood circulation, making it dependent on the energy consumption of specific areas. However, progressive age-related changes in the arteries and veins eventually lead to an increase in chronic hypoxia, im-paired nervous regulation and vascular dystonia, increased blood vessels sclerosis and hyalinosis, and sclerosis of intravascular myogenic structures with loss of their function of blood flow regu-lation, as well as the development of vein thrombosis. As a result, increasing vascular decom-pensation in patients with bladder outlet obstruction results in bladder ischemia and accelerates the decompensation of the lower urinary tract.

Relation of biological activity of mutant forms of recombinant human tumor necrosis factor alpha and accumulation of sphingosine in murine liver.

TNF-alpha induced sphingomyelin hydrolysis by sphingomyelinase and both sphingosine and ceramide generation have been reported to be implicated in a number of TNF-alpha responses, including cytotoxicity and apoptosis. We found that sphingosine, a highly cytotoxic product of enzymatic degradation of sphingomyelin, is accumulated in liver of mice treated with TNF-alpha. To determine the role of sphingosine in TNF-alpha toxicity, TNF-alpha mutants differing in their cytotoxicity to L929 cells as well as haemorrhagic tumor necrosis, tumor regression and lethal toxicity in mice were used in our experiments. The mutants with highest toxicity and tumor-necrotizing activity caused accumulation of sphingosine exceeded its control level 5,5 times in murine liver cells. TNF-alpha variants which caused moderate increase in sphingosine content were significantly less toxic. The observed relationship between toxicity of TNF-alpha mutants, the toxicity of sphingosine, and the extent of its accumulation in murine liver provides evidence to suggest that this sphingomyelin metabolite may be mediator of TNF-alpha-induced cell damage and death.