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HMGB1: A potential target for treatment of benign prostatic hyperplasia
Medical Hypotheses 81 (2013) 892–895
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
HMGB1: A potential target for treatment of benign prostatic hyperplasia q Xue Rui a,b,1, Ma Shengli b,1, Jia Zhankui a, Pi Guofu b, Yang Jinjian a,⇑ a b
Department of Urology, The First Affiliated Hospital of Zhengzhou University, NO.1 Jian She Dong Avenue, Zhengzhou 450002, People’s Republic of China Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, NO.1 Jian She Dong Avenue, Zhengzhou 450002, People’s Republic of China
a r t i c l e
i n f o
Article history: Received 21 May 2013 Accepted 23 July 2013
a b s t r a c t Previous studies have demonstrated an increased incidence of benign prostatic hyperplasia (BPH) in men with prostatitis. In addition to androgens and age, recent studies also pointed to an important role for inflammation in causing and promoting the progression of BPH. Inflammatory infiltrates are frequently observed in prostate tissue specimens, and the degree of inflammation has been correlated with prostate volume and weight. Furthermore, a pro-inflammatory microenvironment is closely related to BPH stromal hyperproliferation and tissue remodeling, although its role in BPH remains unclear. Accumulating evidence indicates that HMGB1 acts as a potent proinflammatory cytokine that contributes to the pathogenesis of many inflammatory and infectious disorders. Experimental studies also reported that HMGB1 promotes cell chemotaxis and proliferation. These observations led us to propose that HMGB1 contributes to the progress of BPH, and that targeting the HMGB1 signaling pathway might be a new strategy to treat prostatic enlargement. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Benign prostatic hyperplasia (BPH) is a common disease among men attending urology clinics [1]. It is defined as prostate gland enlargement secondary to hyperproliferation of stromal and glandular cells, with a predominance of mesenchymal cells. Aging and the presence of androgens are considered to be the primary causes of BPH, although the specific molecular and cellular mechanisms that cause BPH remain unclear [2,3]. Although prostatic inflammation was suggested to participate in the pathogenesis of BPH as early as during the 1930s [4], it only received much attention over the past 10 years. Both histological examinations and epidemiological data suggested that prostatic inflammation was responsible, at least partially, for the pathogenesis, progression, and clinical manifestation of BPH [5–10], and epidemiological studies have demonstrated a chronic inflammatory infiltrate in 43% of men with BPH [11]. Accordingly, BPH has been proposed to be an immunemediated inflammatory disease [9,12–14], which might benefit from antibacterial or anti-inflammatory treatments. High mobility group box 1 (HMGB1) is a highly conserved nuclear protein that functions as a structural co-factor critical for proper transcriptional regulation in somatic cells [15–18]. It can
q
This study was supported by grants from the Youth Foundation of The First Affiliated Hospital of Zhengzhou University. ⇑ Corresponding author. Tel.: +86 0371 66925219. E-mail address: [email protected] (Y. Jinjian). 1 These authors equally contributed to this manuscript. 0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.07.047
be synthesized by nearly all cell types, including activated monocytes, macrophages, neutrophils, and platelets [19–21]. HMGB1 has been detected in both acute and chronic inflammatory conditions [22], where it mediates endotoxin lethality, acute lung injury, and hemorrhagic shock [23–26]. In addition, HMGB1 mediates smooth muscle chemotaxis, neurite outgrowth, and pro-inflammatory responses in endothelial cells [20,21,27,28], as well as participating in the pathogenesis of systemic inflammation after the early mediator response has resolved [23,29]. In most of these cases, unlike the early inflammatory factors, HMGB1 serves as a late-response cytokine. Moreover, it usually exists in the serum for a long time, providing a sufficiently long period for effective treatment of inflammatory disease. Taken together, the available evidence suggests that HMGB1 is an important late inflammatory factor that plays unique roles in inflammation and tissue repair. Considering that both BPH and HMGB1 are associated with inflammation and tissue remodeling, we believe that mechanistic insight into the relationship between HMGB1 and BPH might contribute to the effective treatment of BPH and obstructive symptoms of the lower urinary tract. The hypothesis Given the above indications, we proposed that HMGB1 may be involved in the onset and progression of BPH. The large number of inflammatory cells and necrotic cells that gather in inflammatory sites in BPH patients might release HMGB1 into the extracellular apace either actively or passively, which would result in the
X. Rui et al. / Medical Hypotheses 81 (2013) 892–895
accumulation of HMGB1 in the prostate. The proposed increased level of HMGB1 would stimulate monocytes and endothelial cells to release TNF-a, IL-6, IL-8, and other inflammatory factors, which would trigger inflammation or cause the deterioration of the existing inflammation reaction. These early inflammatory factors would in turn promote the secretion of HMGB1 through the demonstrated positive feedback regulation between themselves and HMGB1 [30]. This process is proposed to increase the expression of endothelial cell adhesion molecules, which also help to amplify and maintain the inflammatory response. In addition, the proposed increase in HMGB1 abundance might also stimulate the proliferation of prostatic stromal smooth muscle cells to serve as a bridge between tissue inflammation and hyperplasia. Therefore, we hypothesize that increased HMGB1 might be a key factor that promotes the development of BPH, and that HMGB1 might also act as a link between BPH and chronic prostatic inflammation.
Discussion Prostatitis and BPH are closely related diseases that are commonly found in men. A survey of 31,689 men in the USA reported prevalence values of 16% and 23.5% for self-reported prostatitis and BPH, respectively. Men reporting a history of BPH had 7.7-fold greater likelihood of a history of prostatitis [31]. REDUCE (REduction by DUtasteride of prostate Cancer Events) and MTOPS (Medical Therapies of Prostate Symptoms) analysis also found that a respective 77.6% and 42.8% of BPH tissue specimens were associated with chronic inflammation [32,33], and that the degree of tissue inflammation was correlated closely with the degree of BPH. Robert et al. [34] also reported that the majority of patients with BPH had inflammatory cells that infiltrated BPH tissue. The observation that the international prostate symptom score (IPSS) and prostate volume were significantly higher in patients with highgrade prostatic inflammation than in otherwise comparable healthy patients [34], suggests that anti-inflammation treatment is one of the targets of treatment of BPH. A study that involved mouse prostate showed that inflammation was evident in all lobes of the prostate that were characterized by BPH, and that this was accompanied by the induction of several inflammatory genes, including those that encode IL-6, IL-8, and COX-2, which induced significant increase in epithelial proliferation and reactive hyperplasia in prostate [35,36]. The above studies suggested that chronic prostate inflammation might be an important factor for BPH, and that it is closely associated with disease progression. The demonstration by Kramer et al. [6] that chronic inflammation is a key condition that causes prostate enlargement and increased symptoms score as well as a major risk of complications suggests that the pro-inflammatory microenvironment may be closely related to BPH stromal hyperproliferation and tissue remodeling. However, although the presence of inflammation infiltrates in prostates is well described, it is not clear when and why chronic inflammation occurs in the prostate [37]. Further exploration of the relationship between chronic inflammation and BPH are required to expand the understanding of BPH pathogenesis and its progress at the level of histology and clinical symptoms. As a late-response inflammatory factor, HMGB1 plays important roles to maintain and amplify inflammatory responses. HMGB1 can be actively released from immune cells, such as macrophages, monocytes, natural killer cells, dendritic cells, endothelial cells, and platelet cells [23,29,38,39]. It is also passively released from necrotic or apoptotic cells [40–44]. Exogenous HMGB1 can act via receptors to activate pro-inflammatory responses in multiple cell types. For instance, HMGB1 induces the maturation of dendritic cells as well as the secretion of inflammatory cytokines [45,46]. After their stimulation with HMGB1, T
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cells release cytokines and appear to have increased proliferation, survival, and Th1 functional polarization [47,48]. Other immune cells, such as monocytes, neutrophils, and natural killer cells, can also be stimulated by HMGB1 to release numerous cytokines and inflammatory mediators [49,50]. Whereas HMGB1 released by necrotic cells can trigger inflammation, the absence of HMGB1 in necrotic cells was associated with a greatly reduced ability to promote inflammation [40]. Given that all of the evidence described above clearly revealed the close relationship between HMGB1 and inflammation (Fig. 1A), we propose that HMGB1 might also promote inflammatory responses during BPH development. More recently, HMGB1 has been implicated in the pathogenesis of inflammatory responses such as sepsis, acute lung injury, epithelial barrier dysfunction, arthritis, and death [41]. This suggests that HMGB1 warrants investigation as a therapeutic target in inflammatory diseases, and therapies that suppress HMGB1 activity might ameliorate the severity of many preclinical inflammatory diseases and reduce their rates of associated mortality. A mouse model of sepsis indicated increased levels of serum HMGB1 from 8 to 32 h after endotoxin treatment, and that administration of antibodies to HMGB1 attenuated endotoxin lethality [23]. Antibodies to HMGB1 also inhibit the development of synovial inflammation and joint swelling in experimental models of arthritis [51,52]. Targeting HMGB1 can attenuate inflammation in acute pancreatitis, and ameliorate hepatic ischemia–reperfusion injury in mice [53]. The classification of strategies that target HMGB1 in inflammatory disease according to their mechanisms of action [54] has deepened our understanding of the function of HMGB1 and increased the likelihood that it is possible to treat BPH by blocking HMGB1. Although no causal relationship has been found between BPH and prostate cancer (PC), there are a number of compelling similarities between the two conditions. These include increasing incidence and prevalence with age, concordant natural history, and hormonal requirements for growth and development. Gnanasekar et al. have summarized the role of HMGB1 in the development of PC; they pointed out that while HMGB1 might have a role in the up-regulation of the expression of androgen receptor (AR) in PC cells, the gene that encodes AR is crucial for the progression of both PC and BPH [55]. In addition, growing evidence that HMGB1 plays a major role in inflammation-induced carcinogenesis supports our hypothesis that HMGB1 might promote inflammation during BPH progression [56,57]. The evidence mentioned above suggests that blocking the action of HMGB1 might provide a promising treatment for both BPH and PC. However, it should also be noted that the precise mechanism by which HMGB1 acts might differ in PC and BPH. Accordingly, effective treatment of the two conditions might require different means of blocking HMGB1. Degryse et al. [20] used chemotaxis, chemokinesis, and wound healing assays to show that HMGB1 can induce migration of rat smooth muscle cells. This supports the proposal that HMGB1 might promote cell proliferation because wound healing requires an accelerated rate of cell growth and division. The release of large amounts of HMGB1 after the damage of endothelial cells will induce a change in the phenotype of smooth muscle cells converted from a contractile to a synthetic phenotype, which is associated with the initiation of cell proliferation and the migration of smooth muscle cells across the endothelial layer to the underlying tissue. It is likely that the synthesis of HMGB1 by activated macrophages during atherogenesis promotes the proliferation and migration of vascular smooth muscle cells. Rat models of myocardial infarction indicated that HMGB1 induced cardiac regeneration and improved cardiac function [58]. Moreover, HMGB1 increased the expression of anti-apoptotic proteins in the nervous system, and promoted tissue regeneration [59]. Notably, the effects of HMGB1 in promoting cell migration and proliferation were also
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X. Rui et al. / Medical Hypotheses 81 (2013) 892–895
Fig. 1. The inflammatory effects of HMGB1 contribute to the onset and progression of BPH. (A) HMGB1 causes inflammation. HMGB1 can be secreted by innate immune cells, apoptotic cells, or necrotic cells. The released HMGB1 stimulates the secretion of pro-inflammatory cytokines and elicits injurious inflammatory responses, and the pro-inflammatory cytokines in turn stimulate the secretion of HMGB1. (B) HMGB1 contributes to the onset and progression of BPH. Positive feedback between HMGB1 and inflammation promotes cell proliferation, migration, and growth, while inhibiting apoptosis. Together, these stimulative and inhibitory effects promote the progression of BPH. (DC, dendritic cell; NK, natural killer).
mediated by pro-inflammatory factors in these models. Taken together, these sources of evidence strongly point to HMGB1 as a potent mediator of tissue repair after mechanical injury or inflammation, and suggest that HMGB1 might thus contribute to the onset of BPH (Fig. 1B). Notwithstanding this evidence, the results of certain studies are inconsistent with a role for HMGB1 in promoting the progression of inflammatory diseases. A recent review written by Kang et al. reported that HMGB1 has paradoxical roles in promoting both cell survival and cell death during cancer development and therapy [60]. The authors pointed out that the function of HMGB1 in cancer development depends on the stages of cancer development, the pathway that acts downstream of HMGB1 action, as well as the factors that interact with HMGB1. This range of factors involved complicates clarification of the relative importance of the contributing effects. Given the complicated etiology of HMGB1 in BPH, it is possible that HMGB1 plays a dual role during the development of this disease. However, identification of the specific mechanism(s) involved requires further investigation. The evidence that indicates the close relationship between the inflammation of prostate tissue and the occurrence and development of BPH, as well as the ability of HMGB1 to promote inflammation, cellular migration, and proliferation leads us to hypothesize that HMGB1 might contribute to the progression of BPH. However, we still cannot exclude the possibility that HMGB1 might have different effects during the development of BPH. Regardless of the mechanism(s) involved, the important role played by HMGB1 during the progression of BPH implies that HMGB1 should provide an effective pharmacological drug target for BPH treatment.
Conflict of interest statement None declared.
Acknowledgments This study was supported by grants from the Youth Foundation of the First Affiliated Hospital of Zhengzhou University. We thank Dr. Lihong Chen for her assistance in editing the manuscript.
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Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
HMGB1: A potential target for treatment of benign prostatic hyperplasia q Xue Rui a,b,1, Ma Shengli b,1, Jia Zhankui a, Pi Guofu b, Yang Jinjian a,⇑ a b
Department of Urology, The First Affiliated Hospital of Zhengzhou University, NO.1 Jian She Dong Avenue, Zhengzhou 450002, People’s Republic of China Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, NO.1 Jian She Dong Avenue, Zhengzhou 450002, People’s Republic of China
a r t i c l e
i n f o
Article history: Received 21 May 2013 Accepted 23 July 2013
a b s t r a c t Previous studies have demonstrated an increased incidence of benign prostatic hyperplasia (BPH) in men with prostatitis. In addition to androgens and age, recent studies also pointed to an important role for inflammation in causing and promoting the progression of BPH. Inflammatory infiltrates are frequently observed in prostate tissue specimens, and the degree of inflammation has been correlated with prostate volume and weight. Furthermore, a pro-inflammatory microenvironment is closely related to BPH stromal hyperproliferation and tissue remodeling, although its role in BPH remains unclear. Accumulating evidence indicates that HMGB1 acts as a potent proinflammatory cytokine that contributes to the pathogenesis of many inflammatory and infectious disorders. Experimental studies also reported that HMGB1 promotes cell chemotaxis and proliferation. These observations led us to propose that HMGB1 contributes to the progress of BPH, and that targeting the HMGB1 signaling pathway might be a new strategy to treat prostatic enlargement. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Benign prostatic hyperplasia (BPH) is a common disease among men attending urology clinics [1]. It is defined as prostate gland enlargement secondary to hyperproliferation of stromal and glandular cells, with a predominance of mesenchymal cells. Aging and the presence of androgens are considered to be the primary causes of BPH, although the specific molecular and cellular mechanisms that cause BPH remain unclear [2,3]. Although prostatic inflammation was suggested to participate in the pathogenesis of BPH as early as during the 1930s [4], it only received much attention over the past 10 years. Both histological examinations and epidemiological data suggested that prostatic inflammation was responsible, at least partially, for the pathogenesis, progression, and clinical manifestation of BPH [5–10], and epidemiological studies have demonstrated a chronic inflammatory infiltrate in 43% of men with BPH [11]. Accordingly, BPH has been proposed to be an immunemediated inflammatory disease [9,12–14], which might benefit from antibacterial or anti-inflammatory treatments. High mobility group box 1 (HMGB1) is a highly conserved nuclear protein that functions as a structural co-factor critical for proper transcriptional regulation in somatic cells [15–18]. It can
q
This study was supported by grants from the Youth Foundation of The First Affiliated Hospital of Zhengzhou University. ⇑ Corresponding author. Tel.: +86 0371 66925219. E-mail address: [email protected] (Y. Jinjian). 1 These authors equally contributed to this manuscript. 0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.07.047
be synthesized by nearly all cell types, including activated monocytes, macrophages, neutrophils, and platelets [19–21]. HMGB1 has been detected in both acute and chronic inflammatory conditions [22], where it mediates endotoxin lethality, acute lung injury, and hemorrhagic shock [23–26]. In addition, HMGB1 mediates smooth muscle chemotaxis, neurite outgrowth, and pro-inflammatory responses in endothelial cells [20,21,27,28], as well as participating in the pathogenesis of systemic inflammation after the early mediator response has resolved [23,29]. In most of these cases, unlike the early inflammatory factors, HMGB1 serves as a late-response cytokine. Moreover, it usually exists in the serum for a long time, providing a sufficiently long period for effective treatment of inflammatory disease. Taken together, the available evidence suggests that HMGB1 is an important late inflammatory factor that plays unique roles in inflammation and tissue repair. Considering that both BPH and HMGB1 are associated with inflammation and tissue remodeling, we believe that mechanistic insight into the relationship between HMGB1 and BPH might contribute to the effective treatment of BPH and obstructive symptoms of the lower urinary tract. The hypothesis Given the above indications, we proposed that HMGB1 may be involved in the onset and progression of BPH. The large number of inflammatory cells and necrotic cells that gather in inflammatory sites in BPH patients might release HMGB1 into the extracellular apace either actively or passively, which would result in the
X. Rui et al. / Medical Hypotheses 81 (2013) 892–895
accumulation of HMGB1 in the prostate. The proposed increased level of HMGB1 would stimulate monocytes and endothelial cells to release TNF-a, IL-6, IL-8, and other inflammatory factors, which would trigger inflammation or cause the deterioration of the existing inflammation reaction. These early inflammatory factors would in turn promote the secretion of HMGB1 through the demonstrated positive feedback regulation between themselves and HMGB1 [30]. This process is proposed to increase the expression of endothelial cell adhesion molecules, which also help to amplify and maintain the inflammatory response. In addition, the proposed increase in HMGB1 abundance might also stimulate the proliferation of prostatic stromal smooth muscle cells to serve as a bridge between tissue inflammation and hyperplasia. Therefore, we hypothesize that increased HMGB1 might be a key factor that promotes the development of BPH, and that HMGB1 might also act as a link between BPH and chronic prostatic inflammation.
Discussion Prostatitis and BPH are closely related diseases that are commonly found in men. A survey of 31,689 men in the USA reported prevalence values of 16% and 23.5% for self-reported prostatitis and BPH, respectively. Men reporting a history of BPH had 7.7-fold greater likelihood of a history of prostatitis [31]. REDUCE (REduction by DUtasteride of prostate Cancer Events) and MTOPS (Medical Therapies of Prostate Symptoms) analysis also found that a respective 77.6% and 42.8% of BPH tissue specimens were associated with chronic inflammation [32,33], and that the degree of tissue inflammation was correlated closely with the degree of BPH. Robert et al. [34] also reported that the majority of patients with BPH had inflammatory cells that infiltrated BPH tissue. The observation that the international prostate symptom score (IPSS) and prostate volume were significantly higher in patients with highgrade prostatic inflammation than in otherwise comparable healthy patients [34], suggests that anti-inflammation treatment is one of the targets of treatment of BPH. A study that involved mouse prostate showed that inflammation was evident in all lobes of the prostate that were characterized by BPH, and that this was accompanied by the induction of several inflammatory genes, including those that encode IL-6, IL-8, and COX-2, which induced significant increase in epithelial proliferation and reactive hyperplasia in prostate [35,36]. The above studies suggested that chronic prostate inflammation might be an important factor for BPH, and that it is closely associated with disease progression. The demonstration by Kramer et al. [6] that chronic inflammation is a key condition that causes prostate enlargement and increased symptoms score as well as a major risk of complications suggests that the pro-inflammatory microenvironment may be closely related to BPH stromal hyperproliferation and tissue remodeling. However, although the presence of inflammation infiltrates in prostates is well described, it is not clear when and why chronic inflammation occurs in the prostate [37]. Further exploration of the relationship between chronic inflammation and BPH are required to expand the understanding of BPH pathogenesis and its progress at the level of histology and clinical symptoms. As a late-response inflammatory factor, HMGB1 plays important roles to maintain and amplify inflammatory responses. HMGB1 can be actively released from immune cells, such as macrophages, monocytes, natural killer cells, dendritic cells, endothelial cells, and platelet cells [23,29,38,39]. It is also passively released from necrotic or apoptotic cells [40–44]. Exogenous HMGB1 can act via receptors to activate pro-inflammatory responses in multiple cell types. For instance, HMGB1 induces the maturation of dendritic cells as well as the secretion of inflammatory cytokines [45,46]. After their stimulation with HMGB1, T
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cells release cytokines and appear to have increased proliferation, survival, and Th1 functional polarization [47,48]. Other immune cells, such as monocytes, neutrophils, and natural killer cells, can also be stimulated by HMGB1 to release numerous cytokines and inflammatory mediators [49,50]. Whereas HMGB1 released by necrotic cells can trigger inflammation, the absence of HMGB1 in necrotic cells was associated with a greatly reduced ability to promote inflammation [40]. Given that all of the evidence described above clearly revealed the close relationship between HMGB1 and inflammation (Fig. 1A), we propose that HMGB1 might also promote inflammatory responses during BPH development. More recently, HMGB1 has been implicated in the pathogenesis of inflammatory responses such as sepsis, acute lung injury, epithelial barrier dysfunction, arthritis, and death [41]. This suggests that HMGB1 warrants investigation as a therapeutic target in inflammatory diseases, and therapies that suppress HMGB1 activity might ameliorate the severity of many preclinical inflammatory diseases and reduce their rates of associated mortality. A mouse model of sepsis indicated increased levels of serum HMGB1 from 8 to 32 h after endotoxin treatment, and that administration of antibodies to HMGB1 attenuated endotoxin lethality [23]. Antibodies to HMGB1 also inhibit the development of synovial inflammation and joint swelling in experimental models of arthritis [51,52]. Targeting HMGB1 can attenuate inflammation in acute pancreatitis, and ameliorate hepatic ischemia–reperfusion injury in mice [53]. The classification of strategies that target HMGB1 in inflammatory disease according to their mechanisms of action [54] has deepened our understanding of the function of HMGB1 and increased the likelihood that it is possible to treat BPH by blocking HMGB1. Although no causal relationship has been found between BPH and prostate cancer (PC), there are a number of compelling similarities between the two conditions. These include increasing incidence and prevalence with age, concordant natural history, and hormonal requirements for growth and development. Gnanasekar et al. have summarized the role of HMGB1 in the development of PC; they pointed out that while HMGB1 might have a role in the up-regulation of the expression of androgen receptor (AR) in PC cells, the gene that encodes AR is crucial for the progression of both PC and BPH [55]. In addition, growing evidence that HMGB1 plays a major role in inflammation-induced carcinogenesis supports our hypothesis that HMGB1 might promote inflammation during BPH progression [56,57]. The evidence mentioned above suggests that blocking the action of HMGB1 might provide a promising treatment for both BPH and PC. However, it should also be noted that the precise mechanism by which HMGB1 acts might differ in PC and BPH. Accordingly, effective treatment of the two conditions might require different means of blocking HMGB1. Degryse et al. [20] used chemotaxis, chemokinesis, and wound healing assays to show that HMGB1 can induce migration of rat smooth muscle cells. This supports the proposal that HMGB1 might promote cell proliferation because wound healing requires an accelerated rate of cell growth and division. The release of large amounts of HMGB1 after the damage of endothelial cells will induce a change in the phenotype of smooth muscle cells converted from a contractile to a synthetic phenotype, which is associated with the initiation of cell proliferation and the migration of smooth muscle cells across the endothelial layer to the underlying tissue. It is likely that the synthesis of HMGB1 by activated macrophages during atherogenesis promotes the proliferation and migration of vascular smooth muscle cells. Rat models of myocardial infarction indicated that HMGB1 induced cardiac regeneration and improved cardiac function [58]. Moreover, HMGB1 increased the expression of anti-apoptotic proteins in the nervous system, and promoted tissue regeneration [59]. Notably, the effects of HMGB1 in promoting cell migration and proliferation were also
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Fig. 1. The inflammatory effects of HMGB1 contribute to the onset and progression of BPH. (A) HMGB1 causes inflammation. HMGB1 can be secreted by innate immune cells, apoptotic cells, or necrotic cells. The released HMGB1 stimulates the secretion of pro-inflammatory cytokines and elicits injurious inflammatory responses, and the pro-inflammatory cytokines in turn stimulate the secretion of HMGB1. (B) HMGB1 contributes to the onset and progression of BPH. Positive feedback between HMGB1 and inflammation promotes cell proliferation, migration, and growth, while inhibiting apoptosis. Together, these stimulative and inhibitory effects promote the progression of BPH. (DC, dendritic cell; NK, natural killer).
mediated by pro-inflammatory factors in these models. Taken together, these sources of evidence strongly point to HMGB1 as a potent mediator of tissue repair after mechanical injury or inflammation, and suggest that HMGB1 might thus contribute to the onset of BPH (Fig. 1B). Notwithstanding this evidence, the results of certain studies are inconsistent with a role for HMGB1 in promoting the progression of inflammatory diseases. A recent review written by Kang et al. reported that HMGB1 has paradoxical roles in promoting both cell survival and cell death during cancer development and therapy [60]. The authors pointed out that the function of HMGB1 in cancer development depends on the stages of cancer development, the pathway that acts downstream of HMGB1 action, as well as the factors that interact with HMGB1. This range of factors involved complicates clarification of the relative importance of the contributing effects. Given the complicated etiology of HMGB1 in BPH, it is possible that HMGB1 plays a dual role during the development of this disease. However, identification of the specific mechanism(s) involved requires further investigation. The evidence that indicates the close relationship between the inflammation of prostate tissue and the occurrence and development of BPH, as well as the ability of HMGB1 to promote inflammation, cellular migration, and proliferation leads us to hypothesize that HMGB1 might contribute to the progression of BPH. However, we still cannot exclude the possibility that HMGB1 might have different effects during the development of BPH. Regardless of the mechanism(s) involved, the important role played by HMGB1 during the progression of BPH implies that HMGB1 should provide an effective pharmacological drug target for BPH treatment.
Conflict of interest statement None declared.
Acknowledgments This study was supported by grants from the Youth Foundation of the First Affiliated Hospital of Zhengzhou University. We thank Dr. Lihong Chen for her assistance in editing the manuscript.
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