Role of Oxidative Stress and Inflammation in the Pathogenesis of BPH

Inflammation is a complex phenomenon consisting of humoral (cytokines) and cellular (leukocytes) components. Inflammation can influence the tissue microenvironment through the production of free radicals, COX activity, and NO synthesis, all linked to the deleterious oxidative effect of inflammation on prostatic tissue. These factors can alter protein structure and function, induce gene changes, cause post-translational modifications, including those involved in DNA repair and apoptotic processes, and provoke cellular proliferation.

All these aspects generate an important link between inflammatory processes and the induction of prostatic growth of preneoplastic and neoplastic lesions. Data show that chronic inflammation can induce proliferative events and posttranslational DNA modifications in prostatic tissue through oxidative stress [95]. In fact, repeated tissue damage and oxidative stress related to this event may provoke a compensatory cellular proliferation with the risk of hyperplastic growth or also of neoplastic modifications [96, 97]. It is well accepted that regions of prostatic inflammation can generate free radicals, such as nitric oxide (NO) and various species of oxygen. In particular, macrophages and neutrophil infiltrations provide a source of free radicals that can induce hyperplastic or precancerous transformations through the oxidative stress to the tissue and DNA [96]. A feature of these oxidative stress reactions is the production of arachi-donic acid from membranes, a process associated with the generation of new reactive oxygen radicals [96]. It can also be converted by the COX enzymes to various eico-sanoids, in particular, prostaglandins that have long been recognized as important factors in the regulation of prostatic cell proliferation [96]. Normally, prostate tissue is protected from oxidative stress reactions, free radicals, and highly ROS by the super-oxide-dismutase and the glutathione-S-transferase (GST)-P1 enzyme systems, the body's natural protective mechanisms. It is important that estrogens, through the estrogen receptor b (ERb), appear to influence the protective activity of GST on production of free radicals [ 98] . A modern context highlights that the transplacental transmission of an estrogen signal can promote cancer induction in later life. Estrogens can initiate molecular events, referred to as gene imprinting or gene silencing, that are related to the induction of an inflammatory response within the prostate and to the possibility that inflammation could induce preneoplastic lesions. Estrogens given to neonatal rodents result in a "developmental estrogenization" in which there are developmental defects, including a reduction in prostatic growth. This treatment also results in the development of lobe-specific inflammation, dysplasia, or PIN [97]. The spontaneous inflammatory response that is induced in animals by estrogens can be prevented by increasing soy intake or enhancing the levels of genistein [ 98], Biochemically, phytoestrogens (isoflavones and lignans) are heterocyclic phenols structurally similar to the estrogenic steroids and thus possess estrogenic and anti-estrogenic activity. Because of their weak estrogenic activity, phytoestrogens may (a) act as antiestrogens by competing with the more potent, naturally occurring endogenous estrogens (e.g., 17b estradiol) for binding to the estrogen receptor; (b) inhibit the 5a reductase enzyme; (c) inhibit the aromatase enzyme; (d) inhibit tyrosine-specific protein kinases; and (e) inhibit angiogenesis. Additionally, certain phytoestrogens are antioxidants. Some phytoestrogens affect the topoisomerases, and many phytoestro-gens inhibit the growth of experimental tumors [99],

In this pathogenetic hypothesis, NO and COX activity may both play an important role in determining the association between inflammation and prostate growth. In all the inflammatory cells that arrive in the prostate, the inducible nitric oxide synthase (iNOS) is the principal factor activating reactive nitrogens that can damage cells [100]. Gradini et al. [101] characterized NOS expression in human prostate tissue and, particularly for iNOS, they found an increased immunostaining in the epithelial cells in cases of BPH and more with high grade PIN (HGPIN) and PC, when compared with normal tissue. NO also enhances COX activity, the second factor. COX-2 activity has been detected in all inflammatory cells in the epithelium and interstitial spaces of human prostate tissue and it is increased in proliferative inflammatory lesions, generating proinflammatory prostaglandins [96, 97]. In human BPH tissue, Di Silverio et al. [ 102[ showed that COX-2 inhibition can produce a significant increase in prostatic cell apoptotic activity. The mechanism used by inflammation to influence the development and progression of chronic prostatic diseases (BPH and PC) has been suggested and well supported by scientific evidence.

Three recent reviews on the pathogenesis of BPH have provided an evidence-based thesis that strongly suggests a role for inflammation in the propagation of his-tological BPH [3-104]. Kramer et al. [104] have recently outlined the current state of knowledge in regard to the influence of inflammation on the pathogenesis of BPH. Chronic inflammatory infiltrates, mainly composed of chronically activated T cells and macrophages, are frequently associated with BPH nodules [31-33]. These infiltrating cells are responsible for the production of cytokines (IL-2 and IFN-g) which may support fibromuscular growth in BPH [104]. Immigration of T cells into the area is attracted by increased production of proinflammatory cytokines such as IL-6, -8, and -15 [3, 103, 105[ . Surrounding cells become targets and are then killed by unknown mechanisms, leaving behind vacant spaces that are replaced by fibromus-cular nodules with a specific pattern of a Th0/Th3 type of immune response [44],

In situ studies demonstrated elevated expression of proinflammatory cytokines in BPH. IL-6, -8, and -17 may perpetuate chronic immune response in BPH and induce fibromuscular growth by an autocrine or paracrine loop [44, 106] or via induction of COX-2 expression [107]. Immune reaction may be activated via Toll-like receptor (TLR) signaling and mediated by macrophages and T cells [ 106]. Conversely, anti-inflammatory factors such as macrophage inhibitory cytokine-1 (MIC-1) [108]

may be decreased in symptomatic BPH tissues. Animal models provided evidence for the presence of unique T-cell subsets which may suppress autoimmunity in healthy Sprague-Dawley rats resistant to chronic nonbacterial prostatitis [ 109] . Based on the available scientific evidence, it is highly likely that age-dependent weakening of the immune system, coupled with modified hormonal secretion, leads to the deterioration of a postulated population of suppressor cells. This decline in T suppressor cells population, which actively suppresses the recognition of prostatic antigens, leads to gradual infiltration of the prostate by lymphocytes and subsequent cascade of events resulting in BPH [110].

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