Table 3.
Chronological summary of the pre-clinical immunohistochemical studies about radio-induced toxicity on the normal bladder.
| References | Animal model (strain) | Dose set-up | Endpoint (method) | Toxicity timing after RT | Findings |
|---|---|---|---|---|---|
| Stewart et al. (41) |
Female mouse (C3H/Hen Af-nu+) | 10-30 Gy in 1 fr. delivered by a 250 kV X-rays machine through a ventral beam | Morphological changes (hematoxylin eosin staining) | 2 weeks: no changes 7–12 months: epithelial denudation, hyperplasia, necrosis, fibrosis |
The late damage was characterized by epithelial denudation and focal hyperplasia; fibrosis and ulceration were also detectable at higher doses (20–30 Gy) |
| Vale et al. (44) |
Female rat (Wistar) | 10, 15, 20, 25 Gy in 1fr. delivered by Pantak 320- kV X-ray generator | Morphological changes (H&E, toluidine blue staining) | 6 months | Evidence of increase mast cell density. Fibrosis in 9/18 rats |
| Crowe et al. (54) |
Female rat (Wistar) | 15 and 25 Gy in 1 fr. delivered by Pantak HF 320 X-ray generator | Changes in neuropeptides | 6 months | Increase in the density of NPY, SP- and TH-immunoreactive nerves in the urinary bladder |
| Kraft et al. (55) |
Mouse (sex n.a.) (C3H/Hen Af-nu+ and C3H/Neu) | 25 or 19 Gy (ED80 40 weeks after RT) | Morphological changes (TGF-β expression and collagen content) | Increase in TGF-β: 90–360 days Increase in collagen I and III: >180 days |
TGF-beta expression and connective tissue metabolism were important factors determining reduced bladder function after irradiation |
| Kruse et al. (56) |
Female mouse (C3H/Hen Af-nu+) | 20 Gy to rectum 16 Gy to kidney delivered in 1 fr. by 250-kV X-ray | Telangiectasia (microarray analysis of RNA isolated from pre-irradiated kidney/ rectum) | 10–20 weeks | Identification of genes expressed in tissues with manifest vascular damage |
| Kanai et al. (57) |
Rat (Sprague-Dawley) Mouse (nNOS−/−, iNOS−/−, eNOS−/−, C57BL10) |
0–50 Gy in 1 or more fr. (1–3 days interval) delivered by 6 MeV linac | Umbrella cells ulceration | n.a. | mtNOS was in the cardiomyocytes and urothelial cells, and can be either protective or detrimental |
| Jaal et al. (49, 50) |
Female mouse (C3H/Neu) | 20 Gy in 1fr. delivered by Seifert Isovolt 320/20 X-ray machine | Morphological changes (ICAM-1 expression) | Increasing signal at day 2–4 and 16–28 Permanent signal between 90–360 days |
Irradiation induces significant early and late deregulation in ICAM-1 expression levels, preceding bladder functional response |
| Jaal et al. (58) |
Female Mouse (C3H/Neu) | 20 Gy in 1fr. delivered by Seifert Isovolt 320/20 X-ray machine | Vasodilatation (COX-2 in blood vessels) | Early: 4–16 days Late: 90–360 days |
COX-2 dependent inflammatory response in the bladder wall during the early phase after radiation |
| Jaal et al. (59) |
Female mouse (C3H/Neu) | 20 Gy in 1fr. delivered by Seifert Isovolt 320/20 X-ray machine | Decrease in n° of umbrella cells (UP-III) | Early phase: 0–31 days Initial late phase: 90, 120 days |
Irradiation resulted in morphological impairment of the urothelial barrier |
| Jaal et al. (60) |
Female Mouse (C3H/Neu) | 20 Gy in 1fr. delivered by Seifert Isovolt 320/20 X-ray machine | Amount of collagen (Masson's Trichrome) | In the entire late phase, but most pronounced at day 120 and 180 | Suggested neovascularization in the late phase of radiation-induced bladder damage |
| Soler et al. (61) |
Female rat (Lewis) | 20 Gy in 1fr. delivered by Cesium isotope-based irradiator collimated by shield on bladder | Amount of collagen (Masson's Trichrome) and vascularization (VonWillebrand factor) | 1.5 and 3 months | Anti-Angiogenesis therapy is proposed to prevent and/or treat the pathology of radiation cystitis |
| Xu et al. (62) |
Male mouse (NCRNU) | 5 Gy in 5 fr. delivered by 250 kV X-ray machine | Ultrastructural and mitochondrial damage | 60 days | Parthenolide enhanced radiosensitivity of prostate tumors but protects healthy tissues (bladder) from radiation |
| Ozbilgin et al. (63) |
Male mouse (Swiss Albino) | 10 Gy in 1 fr. delivered by Co60 RT | Morphological changes (H&E), POMC immunoreactivity | 24 h, 48 h, and 7 days | No morphological alterations. Expression of POMC on the urothelium seems to spare bladder from radiation injuries |
| Ozbilgin et al. (64) |
Male mouse (Swiss Albino) | 10 Gy in 1 fr. delivered by Co60 RT | Reaction of versican and HB-EGF | 7 days | Increase of versican and HB-EGF concentrations may play a role in the side effects of RT |
| Ozbilgin et al. (65) |
Male mouse (Swiss Albino) | 10 Gy in 1 fr. delivered by Co60 RT | COX-1 and COX-2 immunoreactivity | 24 h, 48 h, and 7 days | The expression of COX-1 and COX-2 seems to prevent bladder damage from radiation |
| Giglio et al. (53) |
Female rat (Sprague–Dawley) | 20 Gy in 1fr. delivered by 6 MeV linac through two side- field | Extensive immuno-histochemical characterization | 16 h−14 days | Irradiation may suppress important immunoregulatory pathways |
| Rajaganapathy et al. (51) |
Female rat (Sprague-Dawley) | 20, 30, 40 Gy in 1fr. delivered by SARRP unit through three ventral beams | Morphological changes (H&E) | Early response: 6 weeks | Evidence of degenerative type epithelial changes, urothelial swelling and hyperplasia |
| Zwaans et al. (52) |
Female Mouse (C3H/HeN) | 20 Gy in 1fr. delivered by SARRP unit through two ventral beams | Morphological changes (H&E) Fibrosis (Masson Trichrome) Mast cells (toluidine blue staining) |
Starting at 17 weeks after treatment | Pathological changes included fibrosis, inflammation, urothelial thinning, and necrosis. The radiation exposure attenuated the long-term urothelial integrity |
RT, radiotherapy; ICAM-1, intercellular adhesion molecule 1; mtNOS, mitochondrial nitric oxide synthase; COX, cyclooxygenase; UP-III, uroplakin-III; POMC, Proopiomelanocortin; HB-EGF, heparin-binding EGF-like growth factor; ICAM-1, irradiation on intercellular adhesion molecule 1; H&E, Hematoxylin & Eosin; SARRP, small animal radiation research platform.