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Cystitis: from urothelial cell biology to clinical applications.

Lee G, Romih R, Zupančič D - Biomed Res Int (2014)

Bottom Line: The course of disease is often chronic or recurrent.However, many studies have demonstrated that urothelial dysfunction plays a crucial role.Additionally we review haemorrhagic cystitis with one of the leading causative agents being chemotherapeutic drug cyclophosphamide and summarise its management strategies.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Dankook University College of Medicine, 359 Manghyang-ro, Cheonan 330-715, Republic of Korea.

ABSTRACT
Cystitis is a urinary bladder disease with many causes and symptoms. The severity of cystitis ranges from mild lower abdominal discomfort to life-threatening haemorrhagic cystitis. The course of disease is often chronic or recurrent. Although cystitis represents huge economical and medical burden throughout the world and in many cases treatments are ineffective, the mechanisms of its origin and development as well as measures for effective treatment are still poorly understood. However, many studies have demonstrated that urothelial dysfunction plays a crucial role. In the present review we first discuss fundamental issues of urothelial cell biology, which is the core for comprehension of cystitis. Then we focus on many forms of cystitis, its current treatments, and advances in its research. Additionally we review haemorrhagic cystitis with one of the leading causative agents being chemotherapeutic drug cyclophosphamide and summarise its management strategies. At the end we describe an excellent and widely used animal model of cyclophosphamide induced cystitis, which gives researches the opportunity to get a better insight into the mechanisms involved and possibility to develop new therapy approaches.

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Related in: MedlinePlus

Epinephrine treatment preserves UPII expression in rat urinary bladder 24 hours after cyclophosphamide injection. UPII expression (brown) is a well-established transitional urothelial marker that is strongly expressed along the mucosal area in dilated ureter (red circle). (a) Cyclophosphamide injected rats showed a decrease or loss of UPII expression. (b) Urethral obstructed and -treated rats at 24 hours after cyclophosphamide injection revealed a significant decrease or loss of UPII expression. (c) Intravesical epinephrine treated rats after cyclophosphamide injection showed much better expression pattern of UPII along the bladder mucosa. L: lumen of the urinary bladder or of the ureter. Scale bars (a–c) = 1000 μm and (a′–c′) = 200 μm. Reprinted from Kyung et al., 2012 [58], with permission of Springer-Verlag.
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fig2: Epinephrine treatment preserves UPII expression in rat urinary bladder 24 hours after cyclophosphamide injection. UPII expression (brown) is a well-established transitional urothelial marker that is strongly expressed along the mucosal area in dilated ureter (red circle). (a) Cyclophosphamide injected rats showed a decrease or loss of UPII expression. (b) Urethral obstructed and -treated rats at 24 hours after cyclophosphamide injection revealed a significant decrease or loss of UPII expression. (c) Intravesical epinephrine treated rats after cyclophosphamide injection showed much better expression pattern of UPII along the bladder mucosa. L: lumen of the urinary bladder or of the ureter. Scale bars (a–c) = 1000 μm and (a′–c′) = 200 μm. Reprinted from Kyung et al., 2012 [58], with permission of Springer-Verlag.

Mentions: Cyclophosphamide (2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,2,3-oxazaphosphorine 2-oxide) was first introduced as an antineoplastic agent in 1958 [64] and since then numerous reports have been published concerning haemorrhagic cystitis, a side effect not observed with other alkylating agents. Currently cyclophosphamide is still widely used in chemotherapy of B cell malignant diseases and some solid tumours, conditioning before bone marrow transplantation, and in the treatment of certain immunoinflammatory conditions, for example, Wegener's granulomatosis, rheumatoid arthritis, and systemic lupus erythematosus [65, 66]. Cyclophosphamide side effects depend on the dosage of cyclophosphamide used and can affect up to 75% of the patients receiving a high intravenous dose. The frequent side effects of cyclophosphamide in the urinary bladder range from irritative voiding symptoms, urinary frequency, dysuria, urgency, suprapubic discomfort, and strangury, with microhematuria, to the potentially life-threatening complication of haemorrhagic cystitis [63, 67]. Cyclophosphamide is metabolized in the liver and possibly in the kidney to 4-hydroxy metabolites (e.g., phosphoramide mustard, PAM, and acrolein) which are renally excreted and stored in the urinary bladder until voiding [68, 69]. PAM is the primary chemotherapeutic metabolite but it has minimal effects on the bladder, while acrolein was recognised as the causative agent in cyclophosphamide induced haemorrhagic cystitis [70]. Acrolein is a highly reactive aldehyde and the mechanism by which acrolein reaches the bladder is unclear, although it is suggested that it might be formed in the lumen of the bladder. Effects of acrolein on the bladder wall are contributed to its contact with umbrella cells and include necrosis, desquamation, oedema, ulceration, neovascularization, and haemorrhage [71]. The therapeutic targets in cyclophosphamide induced haemorrhagic cystitis are dysuria or micturition symptoms and massive haematuria. Dysuria, frequent voiding, and urgency may be controlled with medications, but massive haematuria is a life-threatening symptom and should be immediately controlled. Hyperhydration, bladder irrigation, and agents that can detoxify cyclophosphamide such as Mesna (2-mercaptoethane sodium sulphonate) have been the most frequently used prophylactic measures to prevent treatment-related cystitis but are not always effective [72]. In the search for new prevention and treatment approaches hyperbaric oxygen therapy, flavonoids or polyphenols, and melatonin are suggested as supportive treatment, but further studies are required for their translation into clinic [59, 73, 74]. Another promising clinical prophylactic agent is the epinephrine, which is a very important medicine for controlling vascular bleeding and the function of the sympathetic action. Interestingly, epinephrine also decreases the incidence and severity of cyclophosphamide induced cystitis in rats and has even a greater protective effect than Mesna [75]. The research team of Lee has recently reported that intravesical application of epinephrine has an attenuating effect on uroplakin expression, submucosal edema, and hemorrhage in cyclophosphamide induced rat cystitis [58, 76] (Figure 2). Concurrently, intravesical epinephrine preserved both subtypes of alpha1A- and alpha1B-adrenergic receptor expressions in urinary bladder [58]. Before the clinical application of intravesical epinephrine therapy for cyclophosphamide induced haemorrhagic cystitis, one must consider some hypothetical weak points. First, since α-adrenergic stimulation produces relaxation in the bladder body and contraction in bladder neck or prostatic urethra [77], delayed voiding or acute urinary retention can occur. Second, to expect optimal therapeutic effects through intravesical instillation therapy, it is very important to hold the intravesically injected epinephrine within the bladder for maximal absorption. However, exposure to prolonged stagnant urine also poses a risk of longer contact with toxic metabolites of cyclophosphamide. Third, vigorous diuresis or continuous urinary bladder irrigation and frequent urination cannot sustain the therapeutic dosage of intravesically instilled epinephrine and can therefore weaken the effect of the treatment [58].


Cystitis: from urothelial cell biology to clinical applications.

Lee G, Romih R, Zupančič D - Biomed Res Int (2014)

Epinephrine treatment preserves UPII expression in rat urinary bladder 24 hours after cyclophosphamide injection. UPII expression (brown) is a well-established transitional urothelial marker that is strongly expressed along the mucosal area in dilated ureter (red circle). (a) Cyclophosphamide injected rats showed a decrease or loss of UPII expression. (b) Urethral obstructed and -treated rats at 24 hours after cyclophosphamide injection revealed a significant decrease or loss of UPII expression. (c) Intravesical epinephrine treated rats after cyclophosphamide injection showed much better expression pattern of UPII along the bladder mucosa. L: lumen of the urinary bladder or of the ureter. Scale bars (a–c) = 1000 μm and (a′–c′) = 200 μm. Reprinted from Kyung et al., 2012 [58], with permission of Springer-Verlag.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
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fig2: Epinephrine treatment preserves UPII expression in rat urinary bladder 24 hours after cyclophosphamide injection. UPII expression (brown) is a well-established transitional urothelial marker that is strongly expressed along the mucosal area in dilated ureter (red circle). (a) Cyclophosphamide injected rats showed a decrease or loss of UPII expression. (b) Urethral obstructed and -treated rats at 24 hours after cyclophosphamide injection revealed a significant decrease or loss of UPII expression. (c) Intravesical epinephrine treated rats after cyclophosphamide injection showed much better expression pattern of UPII along the bladder mucosa. L: lumen of the urinary bladder or of the ureter. Scale bars (a–c) = 1000 μm and (a′–c′) = 200 μm. Reprinted from Kyung et al., 2012 [58], with permission of Springer-Verlag.
Mentions: Cyclophosphamide (2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,2,3-oxazaphosphorine 2-oxide) was first introduced as an antineoplastic agent in 1958 [64] and since then numerous reports have been published concerning haemorrhagic cystitis, a side effect not observed with other alkylating agents. Currently cyclophosphamide is still widely used in chemotherapy of B cell malignant diseases and some solid tumours, conditioning before bone marrow transplantation, and in the treatment of certain immunoinflammatory conditions, for example, Wegener's granulomatosis, rheumatoid arthritis, and systemic lupus erythematosus [65, 66]. Cyclophosphamide side effects depend on the dosage of cyclophosphamide used and can affect up to 75% of the patients receiving a high intravenous dose. The frequent side effects of cyclophosphamide in the urinary bladder range from irritative voiding symptoms, urinary frequency, dysuria, urgency, suprapubic discomfort, and strangury, with microhematuria, to the potentially life-threatening complication of haemorrhagic cystitis [63, 67]. Cyclophosphamide is metabolized in the liver and possibly in the kidney to 4-hydroxy metabolites (e.g., phosphoramide mustard, PAM, and acrolein) which are renally excreted and stored in the urinary bladder until voiding [68, 69]. PAM is the primary chemotherapeutic metabolite but it has minimal effects on the bladder, while acrolein was recognised as the causative agent in cyclophosphamide induced haemorrhagic cystitis [70]. Acrolein is a highly reactive aldehyde and the mechanism by which acrolein reaches the bladder is unclear, although it is suggested that it might be formed in the lumen of the bladder. Effects of acrolein on the bladder wall are contributed to its contact with umbrella cells and include necrosis, desquamation, oedema, ulceration, neovascularization, and haemorrhage [71]. The therapeutic targets in cyclophosphamide induced haemorrhagic cystitis are dysuria or micturition symptoms and massive haematuria. Dysuria, frequent voiding, and urgency may be controlled with medications, but massive haematuria is a life-threatening symptom and should be immediately controlled. Hyperhydration, bladder irrigation, and agents that can detoxify cyclophosphamide such as Mesna (2-mercaptoethane sodium sulphonate) have been the most frequently used prophylactic measures to prevent treatment-related cystitis but are not always effective [72]. In the search for new prevention and treatment approaches hyperbaric oxygen therapy, flavonoids or polyphenols, and melatonin are suggested as supportive treatment, but further studies are required for their translation into clinic [59, 73, 74]. Another promising clinical prophylactic agent is the epinephrine, which is a very important medicine for controlling vascular bleeding and the function of the sympathetic action. Interestingly, epinephrine also decreases the incidence and severity of cyclophosphamide induced cystitis in rats and has even a greater protective effect than Mesna [75]. The research team of Lee has recently reported that intravesical application of epinephrine has an attenuating effect on uroplakin expression, submucosal edema, and hemorrhage in cyclophosphamide induced rat cystitis [58, 76] (Figure 2). Concurrently, intravesical epinephrine preserved both subtypes of alpha1A- and alpha1B-adrenergic receptor expressions in urinary bladder [58]. Before the clinical application of intravesical epinephrine therapy for cyclophosphamide induced haemorrhagic cystitis, one must consider some hypothetical weak points. First, since α-adrenergic stimulation produces relaxation in the bladder body and contraction in bladder neck or prostatic urethra [77], delayed voiding or acute urinary retention can occur. Second, to expect optimal therapeutic effects through intravesical instillation therapy, it is very important to hold the intravesically injected epinephrine within the bladder for maximal absorption. However, exposure to prolonged stagnant urine also poses a risk of longer contact with toxic metabolites of cyclophosphamide. Third, vigorous diuresis or continuous urinary bladder irrigation and frequent urination cannot sustain the therapeutic dosage of intravesically instilled epinephrine and can therefore weaken the effect of the treatment [58].

Bottom Line: The course of disease is often chronic or recurrent.However, many studies have demonstrated that urothelial dysfunction plays a crucial role.Additionally we review haemorrhagic cystitis with one of the leading causative agents being chemotherapeutic drug cyclophosphamide and summarise its management strategies.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Dankook University College of Medicine, 359 Manghyang-ro, Cheonan 330-715, Republic of Korea.

ABSTRACT
Cystitis is a urinary bladder disease with many causes and symptoms. The severity of cystitis ranges from mild lower abdominal discomfort to life-threatening haemorrhagic cystitis. The course of disease is often chronic or recurrent. Although cystitis represents huge economical and medical burden throughout the world and in many cases treatments are ineffective, the mechanisms of its origin and development as well as measures for effective treatment are still poorly understood. However, many studies have demonstrated that urothelial dysfunction plays a crucial role. In the present review we first discuss fundamental issues of urothelial cell biology, which is the core for comprehension of cystitis. Then we focus on many forms of cystitis, its current treatments, and advances in its research. Additionally we review haemorrhagic cystitis with one of the leading causative agents being chemotherapeutic drug cyclophosphamide and summarise its management strategies. At the end we describe an excellent and widely used animal model of cyclophosphamide induced cystitis, which gives researches the opportunity to get a better insight into the mechanisms involved and possibility to develop new therapy approaches.

Show MeSH
Related in: MedlinePlus