Arab Journal of Gastroenterology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Arab Journal of Gastroenterology journal homepage: www.elsevier.com/locate/ajg
Original Article
Colonic mucosal expression of heat-shock proteins may have a potential prognostic value in ulcerative colitis Abdel Raouf Abou El Azm a, Mohamed Yousef a, Abdelrahman Kobtan a, Aymen Awad b, Galal Elkassas a, Asem Elfert a,⇑ a b
Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt Department of Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt
a r t i c l e
i n f o
Article history: Received 11 August 2014 Accepted 28 November 2014 Available online xxxx Keywords: Ulcerative colitis Heat-shock proteins HSP70 HSP90 Colonic dysplasia
a b s t r a c t Background and study aims: Ulcerative colitis (UC) is a lifelong, chronic, progressive, and relapsing inflammatory disease. Endoscopy with biopsies is the mainstay in diagnosis and assessment. The development of biomarkers is important for the diagnosis and follow-up of UC. We investigated the expression of molecular chaperones/heat-shock proteins (HSP70 and HSP90) in relation to the grades of inflammation and dysplasia in patients with UC before and after treatment. Patients and methods: A total of 104 naïve patients with UC of varying severity were admitted to the Department of Tropical Medicine and Infectious Diseases, Tanta University Hospital. Ten biopsies from the healthy mucosa of patients with irritable bowel syndrome (IBS) served as a control. Disease activity was assessed clinically using the Mayo score system. Endoscopic mucosal biopsies were taken at diagnosis and 6 months after treatment. Histopathological activity was graded for inflammation and dysplasia. Immunohistochemistry was used to determine the percentage of cells positive for HSPs. The results were expressed in a semiquantitative scale. Results: The expression of both HSP70 and HSP90 increased in patients with UC at the time of disease activity, and it decreased after treatment and remission. There was a significant correlation between the expression of both proteins and the grades of dysplasia as well as inflammation (P < 0.05). Strong expression of HSPs that persisted after treatment has been associated with cases of true dysplasia. Conclusions: The results indicated that HSP70 and HSP90 had the potential for assessment of the activity and prognosis of UC. They can also predict the presence of dysplasia and differentiate it from reactive atypia. Larger studies are needed to confirm this diagnostic and prognostic value of HSPs. Ó 2015 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved.
Introduction Ulcerative colitis (UC) is a chronic, progressive, and relapsing inflammatory disorder characterised by damage of the large bowel mucosa and extraintestinal autoimmune comorbidities. It represents a lifelong disorder with high morbidity and potential mortality. It has a risk of transforming into colorectal cancer [1,2]. Endoscopic biopsies are the mainstay in diagnosis, assessment of disease activity, and monitoring treatment. However, the need for reliable surrogate markers of intestinal inflammation and/or malignant transformation still exists [3]. Heat-shock proteins (HSPs) play a significant role in cell proliferation, differentiation, and oncogenesis [4–6]. They are constitutively and gradually expressed in a broad range of normal ⇑ Corresponding author at: Department of Tropical Medicine and Infectious Diseases, Tanta University, Tanta 31527, Egypt. E-mail address: [email protected] (A. Elfert).
tissues and neoplasms, and their expression has been assessed as markers of dysplasia [7–10]. The expression of certain HSPs can be correlated with the carcinogenic process [11,12] as well as with the degree of cell proliferation and differentiation [13]; moreover, they have been implicated in the regulation of apoptosis [14]. Therefore, our aim was, importantly, to study the expression of HSPs in relation to the degree of inflammation and dysplasia in patients with UC before and after therapy.
Patients and methods The study was conducted at the Department of Tropical Medicine and Infectious Diseases, Tanta University. A total of 104 naïve patients diagnosed with UC of varying severity were included from October 2011 to August 2013. Patients with colorectal cancer and/or high-grade dysplasia were excluded and referred to surgery.
http://dx.doi.org/10.1016/j.ajg.2015.02.005 1687-1979/Ó 2015 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Abou El Azm AR et al. Colonic mucosal expression of heat-shock proteins may have a potential prognostic value in ulcerative colitis. Arab J Gastroenterol (2015), http://dx.doi.org/10.1016/j.ajg.2015.02.005
2
A.R. Abou El Azm et al. / Arab Journal of Gastroenterology xxx (2015) xxx–xxx
Endoscopic mucosal biopsies were obtained for all patients at diagnosis and 6 months after treatment irrespective of the response. Ten apparently healthy subjects served as the control. They underwent colonoscopy to rule out organic pathology in a diarrhoea-predominant irritable bowel syndrome (IBS). Biopsies were taken to rule out microscopic colitis. Clinically, disease activity was assessed using the Mayo score from 0 to 12 [15]. Endoscopic activity was graded as mild, moderate, and severe according to the Mayo score [16]. Histopathological activity was graded according to a six-grade classification system for inflammation: 0 = structural change only; 1 = chronic inflammation; 2 = lamina propria neutrophils; 3 = neutrophils in epithelium; 4 = crypt destruction; and 5 = erosions or ulcers [17]. Dysplasia represented as HSP expression was graded as mild, moderate, or strong according to Riddell et al. [18]. Patients were treated with mesalazine (5-aminosalicylic acid, 5-ASA) 4 g/day until clinical remission, and then with 2 g/day for 6 months. No patient needed to be treated with steroids. Then, follow-up endoscopy and biopsy was performed for all 104 patients to assess their histological response to therapy. Histopathology was performed at the Department of Pathology, Tanta University Faculty of Medicine.
Fig. 1a. Endoscopic view of a case with mild UC.
Tissue preparations and immunohistochemistry All biopsies were fixed in formalin and embedded in paraffin. Sections of 5-lm thickness were obtained from all paraffin blocks, de-waxed, and rehydrated for immunohistochemical analysis. Immunostaining was performed using an avidin–biotin complex kit (DAKO, Carpentaria, CA, USA), after incubation for 10 min with serum-free protein blocking. Primary antibodies such as antiHSP70 or anti-HSP90 (dilution 1:200, Santa Cruz Biotechnology, Dallas, TX, USA) were added. Appropriate positive controls, as well as nonimmune serum for negative controls, were run concurrently. 3-30 -diaminobenzidine (DAB chromogen solution, DAKO, Glostrup, Denmark) was used as the developer chromogen. Nuclear counterstaining was performed using haematoxylin. A quantitative analysis was used to determine the percentage of cells positive for HSPs in both the epithelium (Ep) and lamina propria (LP) of the colon mucosa. The results were expressed in a semiquantitative scale (: 0%; +: 1–33%; ++: 34–66%; and +++: 67–100%). All the observations were made at a magnification of 400 and the means of duplicate counts were used for statistical analyses.
Fig. 1b. Endoscopic view of a case with moderate UC.
Statistical analyses The collected data were organised, tabulated, and statistically analysed using SPSS version 12. For quantitative data, the mean and standard deviation were calculated. For qualitative data, the number and percentage of distribution were calculated. Chi-square was used as a test of significance. A correlation was performed between the immunohistochemical levels of HSP, disease activity, and epithelial dysplasia before and after treatment, using Pearson’s test. A P-value 0.05) (Tables 2 and 3). Discussion UC is a lifelong, progressive, and relapsing inflammatory disorder characterised by damage of the large bowel mucosa and extraintestinal autoimmune comorbidities [5]. It often develops complications, including toxic megacolon, massive colonic haemorrhage, strictures, fistulas, or abscesses, and it may transform into colon cancer [19,20]. Endoscopy with biopsy is the mainstay in the diagnosis of UC, and it is also important in the assessment of disease activity and monitoring of treatment [3]. The present study showed correlation of endoscopic assessment of the severity of disease with histological grading of colonic inflammation. This was in accordance with previous reports [18–21]. In the present work, we detected that HSP70 and HSP90 were correlated with the degree of inflammation before and after treatment. These findings were in agreement with a previous report [5], which found that HSP90 is upregulated in inflammatory stress. On the contrary, other reports have found that HSP70 expression was suppressed by chronic stress and downregulated in areas of active inflammation [22]. In the current study, the grades of HSP70 and HSP90 expression were positively correlated with the degree of dysplasia before and after therapy. This was in agreement with a few previous reports [5,23]. This was a remarkable finding that may have the potential to lead the search for a surrogate marker of dysplasia in patients with inflammatory bowel disease (IBD).
Fig. 4b. Significant reduction of HSP70 after treatment.
In the present study, we showed a positive correlation with the changes in the grade of dysplasia after treatment. This will have the potential to differentiate between true- and false-positive dysplasia in ordinary histopathological examination, which is usually affected by the presence of a high grade of inflammation. Therefore, the persistence of HSP expression may be remarkable in cases with true dysplasia. This may affect the recommendation of frequent follow-up, and it might affect the treatment decision. The results of the current study showed that HSPs were significantly decreased after treatment and correlated with significant improvement in the degree of inflammation and dysplasia.
Table 3 The relation between HSP70 and HSP90 expression and grades of dysplasia in the studied specimens after treatment. Grades of dysplasia
ve Probably ve Probably +ve +low +moderate
v2 p-value r p-value *
HSP 70
HSP 90
ve
+
++
+++
ve
+
++
+++
40 (38.5%) – – – – 10.336 0.001* 0.745 0.001*
14 (13.5%) 10 (9.6%) 2 (1.9%) – –
8 (7.7%) 2 (1.9%) 6 (5.8%) – –
– – – 4 (3.8%) 4 (3.8%)
34 (38%) – – – – 8.635 0.002* 0.626 0.003*
18 (17%) 4 (3.8%) 4 (3.8%) – –
10 (9.6%) 8 (7.7%) 4 (3.8%) – –
– – – 4 (3.8%) 4 (3.8%)
p < 0.05 is significant.
Please cite this article in press as: Abou El Azm AR et al. Colonic mucosal expression of heat-shock proteins may have a potential prognostic value in ulcerative colitis. Arab J Gastroenterol (2015), http://dx.doi.org/10.1016/j.ajg.2015.02.005
A.R. Abou El Azm et al. / Arab Journal of Gastroenterology xxx (2015) xxx–xxx
This was in agreement with previous reports [4,22], which found that HSP70 and HSP90 were significantly reduced in patients receiving 5-ASA [5]. We can conclude that HSP70 and HSP90 have the potential to assess the disease severity, monitor the response to therapy, and differentiate between true- and false-positive dysplasia. Larger studies are needed to confirm the effectiveness of the clinical use of these markers in the management of patients with UC. Conflict of interest The authors declared that there was no conflict of interest. References [1] Schirbel A, Fiocchi C. Inflammatory bowel disease: established and evolving considerations on its etiopathogenesis and therapy. J Dig Dis 2010;11:266–76. [2] Bessissow T, Lemmens B, Ferrante M, et al. Prognostic value of serologic and histologic markers on clinical relapse in ulcerative colitis patients with mucosal healing. Am J Gastroenterol 2012;107(11):1684–92. [3] Sipponen T. Diagnostics and prognostics of inflammatory bowel disease with fecal neutrophil-derived biomarkers calprotectin and lactoferrin. Dig Dis 2013;31(3–4):336–44. [4] Tomasello G, Bellavia M, Palumbo VD, et al. From gut microflora imbalance to mycobacteria infection: is there a relationship with chronic intestinal inflammatory diseases? Ann Ital Chir 2011;82:361–8. [5] Tomasello G, Sciumé C, Rappa F, et al. HSP10, HSP70, and HSP90 immunohistochemical levels change in ulcerative colitis after therapy. Eur J Histochem 2011;55:210–4. [6] Rappa F, Farina F, Zummo G, et al. HSP-molecular chaperones in cancer biogenesis and tumor therapy: an overview. Anticancer Res 2012;32:5139–50. [7] Weigl E, Kopecˇek P, Raška M, et al. Heat shock proteins in immune reactions. Folia Microbiol 1999;44:561–6. [8] Rutherford SL, Lindquist S. HSP90 as a capacitor for morphological evolution. Nature 1998;396:336–42.
5
[9] Basu S, Binder RJ, Ramalingam T, et al. CD91 is a common receptor for heat shock proteins gp96, HSP90, HSP70, and calreticulin. Immunity 2001;14:303–13. [10] Quintana FJ, Cohen IR. Heat shock proteins as endogenous adjuvants in sterile and septic inflammation. J Immunol 2005;175:2777–82. [11] Hu SE, Zhu XR, Triggs JR, et al. Inflammation-induced, 30 UTR-dependent translational inhibition of HSP70 mRNA impairs intestinal homeostasis. Am J Physiol Gastrointest Liver Physiol 2009;296(5):G1003–11. [12] Liedel JL, Guo Y, Yu Y, et al. Mother’s milk-induced HSP70 expression preserves intestinal epithelial barrier function in an immature rat pup model. Pediatr Res 2011;69(5):395–400. [13] Ludwig D, Stahl M, Ibrahim ME, et al. Enhanced intestinal expression of heat shock protein 70 in patients with inflammatory bowel diseases. Dig Dis Sci 1999;44(7):1440–7. [14] Maynard CL, Elson CO, Hatton RD, et al. Reciprocal interactions of the intestinal microbiota and immune system. Nature 2012;489(7415):231–41. [15] Musch MW, Sugi K, Straus D, et al. Heat shock protein 72 protects against oxidant-induced injury of barrier function of human colonic epithelial Caco2/ bbe cells. Gastroenterology 1999;117(1):115–22. [16] Shroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-ASA therapy for mildly to moderately active ulcerative colitis. A randomized study. NEJM 1987;24213(26):1625–9. [17] Geboes K, Riddell R, Öst A, et al. A reproducible grading scale for histological assessment of inflammation in ulcerative colitis. Gut 2000;47:404–9. [18] Riddell RH, Goldman H, Ransohoff DF, et al. Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications. Hum Pathol 1983;14(11):931–68. [19] Suzuki M, Inoue Y, Tezuka T, et al. Local complications of the intestinal tract in patients with ulcerative colitis. Nihon Rinsho 1999;57(11):2527–31 (abstract). [20] Cosnes J, Gower-Rousseau C, Seksik P, et al. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology 2011;140:1785–94. [21] Feagins LA, Melton SD, Iqbal R, et al. Clinical implications of histologic abnormalities in colonic biopsy specimens from patients with ulcerative colitis in clinical remission. Inflamm Bowel Dis 2013 Jun;19(7):1477–82. [22] Schulz R, Moll UM. Targeting the heat shock protein 90: a rational way to inhibit macrophage migration inhibitory factor function in cancer. Curr Opin Oncol 2014;26(1):108–13. [23] Tao Y, Hart J, Lichtenstein L, et al. Inducible heat shock protein 70 prevents multifocal flat dysplastic lesions and invasive tumors in an inflammatory model of colon cancer. Carcinogenesis 2009;30(1):175–82.
Please cite this article in press as: Abou El Azm AR et al. Colonic mucosal expression of heat-shock proteins may have a potential prognostic value in ulcerative colitis. Arab J Gastroenterol (2015), http://dx.doi.org/10.1016/j.ajg.2015.02.005
Contents lists available at ScienceDirect
Arab Journal of Gastroenterology journal homepage: www.elsevier.com/locate/ajg
Original Article
Colonic mucosal expression of heat-shock proteins may have a potential prognostic value in ulcerative colitis Abdel Raouf Abou El Azm a, Mohamed Yousef a, Abdelrahman Kobtan a, Aymen Awad b, Galal Elkassas a, Asem Elfert a,⇑ a b
Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt Department of Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt
a r t i c l e
i n f o
Article history: Received 11 August 2014 Accepted 28 November 2014 Available online xxxx Keywords: Ulcerative colitis Heat-shock proteins HSP70 HSP90 Colonic dysplasia
a b s t r a c t Background and study aims: Ulcerative colitis (UC) is a lifelong, chronic, progressive, and relapsing inflammatory disease. Endoscopy with biopsies is the mainstay in diagnosis and assessment. The development of biomarkers is important for the diagnosis and follow-up of UC. We investigated the expression of molecular chaperones/heat-shock proteins (HSP70 and HSP90) in relation to the grades of inflammation and dysplasia in patients with UC before and after treatment. Patients and methods: A total of 104 naïve patients with UC of varying severity were admitted to the Department of Tropical Medicine and Infectious Diseases, Tanta University Hospital. Ten biopsies from the healthy mucosa of patients with irritable bowel syndrome (IBS) served as a control. Disease activity was assessed clinically using the Mayo score system. Endoscopic mucosal biopsies were taken at diagnosis and 6 months after treatment. Histopathological activity was graded for inflammation and dysplasia. Immunohistochemistry was used to determine the percentage of cells positive for HSPs. The results were expressed in a semiquantitative scale. Results: The expression of both HSP70 and HSP90 increased in patients with UC at the time of disease activity, and it decreased after treatment and remission. There was a significant correlation between the expression of both proteins and the grades of dysplasia as well as inflammation (P < 0.05). Strong expression of HSPs that persisted after treatment has been associated with cases of true dysplasia. Conclusions: The results indicated that HSP70 and HSP90 had the potential for assessment of the activity and prognosis of UC. They can also predict the presence of dysplasia and differentiate it from reactive atypia. Larger studies are needed to confirm this diagnostic and prognostic value of HSPs. Ó 2015 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved.
Introduction Ulcerative colitis (UC) is a chronic, progressive, and relapsing inflammatory disorder characterised by damage of the large bowel mucosa and extraintestinal autoimmune comorbidities. It represents a lifelong disorder with high morbidity and potential mortality. It has a risk of transforming into colorectal cancer [1,2]. Endoscopic biopsies are the mainstay in diagnosis, assessment of disease activity, and monitoring treatment. However, the need for reliable surrogate markers of intestinal inflammation and/or malignant transformation still exists [3]. Heat-shock proteins (HSPs) play a significant role in cell proliferation, differentiation, and oncogenesis [4–6]. They are constitutively and gradually expressed in a broad range of normal ⇑ Corresponding author at: Department of Tropical Medicine and Infectious Diseases, Tanta University, Tanta 31527, Egypt. E-mail address: [email protected] (A. Elfert).
tissues and neoplasms, and their expression has been assessed as markers of dysplasia [7–10]. The expression of certain HSPs can be correlated with the carcinogenic process [11,12] as well as with the degree of cell proliferation and differentiation [13]; moreover, they have been implicated in the regulation of apoptosis [14]. Therefore, our aim was, importantly, to study the expression of HSPs in relation to the degree of inflammation and dysplasia in patients with UC before and after therapy.
Patients and methods The study was conducted at the Department of Tropical Medicine and Infectious Diseases, Tanta University. A total of 104 naïve patients diagnosed with UC of varying severity were included from October 2011 to August 2013. Patients with colorectal cancer and/or high-grade dysplasia were excluded and referred to surgery.
http://dx.doi.org/10.1016/j.ajg.2015.02.005 1687-1979/Ó 2015 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Abou El Azm AR et al. Colonic mucosal expression of heat-shock proteins may have a potential prognostic value in ulcerative colitis. Arab J Gastroenterol (2015), http://dx.doi.org/10.1016/j.ajg.2015.02.005
2
A.R. Abou El Azm et al. / Arab Journal of Gastroenterology xxx (2015) xxx–xxx
Endoscopic mucosal biopsies were obtained for all patients at diagnosis and 6 months after treatment irrespective of the response. Ten apparently healthy subjects served as the control. They underwent colonoscopy to rule out organic pathology in a diarrhoea-predominant irritable bowel syndrome (IBS). Biopsies were taken to rule out microscopic colitis. Clinically, disease activity was assessed using the Mayo score from 0 to 12 [15]. Endoscopic activity was graded as mild, moderate, and severe according to the Mayo score [16]. Histopathological activity was graded according to a six-grade classification system for inflammation: 0 = structural change only; 1 = chronic inflammation; 2 = lamina propria neutrophils; 3 = neutrophils in epithelium; 4 = crypt destruction; and 5 = erosions or ulcers [17]. Dysplasia represented as HSP expression was graded as mild, moderate, or strong according to Riddell et al. [18]. Patients were treated with mesalazine (5-aminosalicylic acid, 5-ASA) 4 g/day until clinical remission, and then with 2 g/day for 6 months. No patient needed to be treated with steroids. Then, follow-up endoscopy and biopsy was performed for all 104 patients to assess their histological response to therapy. Histopathology was performed at the Department of Pathology, Tanta University Faculty of Medicine.
Fig. 1a. Endoscopic view of a case with mild UC.
Tissue preparations and immunohistochemistry All biopsies were fixed in formalin and embedded in paraffin. Sections of 5-lm thickness were obtained from all paraffin blocks, de-waxed, and rehydrated for immunohistochemical analysis. Immunostaining was performed using an avidin–biotin complex kit (DAKO, Carpentaria, CA, USA), after incubation for 10 min with serum-free protein blocking. Primary antibodies such as antiHSP70 or anti-HSP90 (dilution 1:200, Santa Cruz Biotechnology, Dallas, TX, USA) were added. Appropriate positive controls, as well as nonimmune serum for negative controls, were run concurrently. 3-30 -diaminobenzidine (DAB chromogen solution, DAKO, Glostrup, Denmark) was used as the developer chromogen. Nuclear counterstaining was performed using haematoxylin. A quantitative analysis was used to determine the percentage of cells positive for HSPs in both the epithelium (Ep) and lamina propria (LP) of the colon mucosa. The results were expressed in a semiquantitative scale (: 0%; +: 1–33%; ++: 34–66%; and +++: 67–100%). All the observations were made at a magnification of 400 and the means of duplicate counts were used for statistical analyses.
Fig. 1b. Endoscopic view of a case with moderate UC.
Statistical analyses The collected data were organised, tabulated, and statistically analysed using SPSS version 12. For quantitative data, the mean and standard deviation were calculated. For qualitative data, the number and percentage of distribution were calculated. Chi-square was used as a test of significance. A correlation was performed between the immunohistochemical levels of HSP, disease activity, and epithelial dysplasia before and after treatment, using Pearson’s test. A P-value 0.05) (Tables 2 and 3). Discussion UC is a lifelong, progressive, and relapsing inflammatory disorder characterised by damage of the large bowel mucosa and extraintestinal autoimmune comorbidities [5]. It often develops complications, including toxic megacolon, massive colonic haemorrhage, strictures, fistulas, or abscesses, and it may transform into colon cancer [19,20]. Endoscopy with biopsy is the mainstay in the diagnosis of UC, and it is also important in the assessment of disease activity and monitoring of treatment [3]. The present study showed correlation of endoscopic assessment of the severity of disease with histological grading of colonic inflammation. This was in accordance with previous reports [18–21]. In the present work, we detected that HSP70 and HSP90 were correlated with the degree of inflammation before and after treatment. These findings were in agreement with a previous report [5], which found that HSP90 is upregulated in inflammatory stress. On the contrary, other reports have found that HSP70 expression was suppressed by chronic stress and downregulated in areas of active inflammation [22]. In the current study, the grades of HSP70 and HSP90 expression were positively correlated with the degree of dysplasia before and after therapy. This was in agreement with a few previous reports [5,23]. This was a remarkable finding that may have the potential to lead the search for a surrogate marker of dysplasia in patients with inflammatory bowel disease (IBD).
Fig. 4b. Significant reduction of HSP70 after treatment.
In the present study, we showed a positive correlation with the changes in the grade of dysplasia after treatment. This will have the potential to differentiate between true- and false-positive dysplasia in ordinary histopathological examination, which is usually affected by the presence of a high grade of inflammation. Therefore, the persistence of HSP expression may be remarkable in cases with true dysplasia. This may affect the recommendation of frequent follow-up, and it might affect the treatment decision. The results of the current study showed that HSPs were significantly decreased after treatment and correlated with significant improvement in the degree of inflammation and dysplasia.
Table 3 The relation between HSP70 and HSP90 expression and grades of dysplasia in the studied specimens after treatment. Grades of dysplasia
ve Probably ve Probably +ve +low +moderate
v2 p-value r p-value *
HSP 70
HSP 90
ve
+
++
+++
ve
+
++
+++
40 (38.5%) – – – – 10.336 0.001* 0.745 0.001*
14 (13.5%) 10 (9.6%) 2 (1.9%) – –
8 (7.7%) 2 (1.9%) 6 (5.8%) – –
– – – 4 (3.8%) 4 (3.8%)
34 (38%) – – – – 8.635 0.002* 0.626 0.003*
18 (17%) 4 (3.8%) 4 (3.8%) – –
10 (9.6%) 8 (7.7%) 4 (3.8%) – –
– – – 4 (3.8%) 4 (3.8%)
p < 0.05 is significant.
Please cite this article in press as: Abou El Azm AR et al. Colonic mucosal expression of heat-shock proteins may have a potential prognostic value in ulcerative colitis. Arab J Gastroenterol (2015), http://dx.doi.org/10.1016/j.ajg.2015.02.005
A.R. Abou El Azm et al. / Arab Journal of Gastroenterology xxx (2015) xxx–xxx
This was in agreement with previous reports [4,22], which found that HSP70 and HSP90 were significantly reduced in patients receiving 5-ASA [5]. We can conclude that HSP70 and HSP90 have the potential to assess the disease severity, monitor the response to therapy, and differentiate between true- and false-positive dysplasia. Larger studies are needed to confirm the effectiveness of the clinical use of these markers in the management of patients with UC. Conflict of interest The authors declared that there was no conflict of interest. References [1] Schirbel A, Fiocchi C. Inflammatory bowel disease: established and evolving considerations on its etiopathogenesis and therapy. J Dig Dis 2010;11:266–76. [2] Bessissow T, Lemmens B, Ferrante M, et al. Prognostic value of serologic and histologic markers on clinical relapse in ulcerative colitis patients with mucosal healing. Am J Gastroenterol 2012;107(11):1684–92. [3] Sipponen T. Diagnostics and prognostics of inflammatory bowel disease with fecal neutrophil-derived biomarkers calprotectin and lactoferrin. Dig Dis 2013;31(3–4):336–44. [4] Tomasello G, Bellavia M, Palumbo VD, et al. From gut microflora imbalance to mycobacteria infection: is there a relationship with chronic intestinal inflammatory diseases? Ann Ital Chir 2011;82:361–8. [5] Tomasello G, Sciumé C, Rappa F, et al. HSP10, HSP70, and HSP90 immunohistochemical levels change in ulcerative colitis after therapy. Eur J Histochem 2011;55:210–4. [6] Rappa F, Farina F, Zummo G, et al. HSP-molecular chaperones in cancer biogenesis and tumor therapy: an overview. Anticancer Res 2012;32:5139–50. [7] Weigl E, Kopecˇek P, Raška M, et al. Heat shock proteins in immune reactions. Folia Microbiol 1999;44:561–6. [8] Rutherford SL, Lindquist S. HSP90 as a capacitor for morphological evolution. Nature 1998;396:336–42.
5
[9] Basu S, Binder RJ, Ramalingam T, et al. CD91 is a common receptor for heat shock proteins gp96, HSP90, HSP70, and calreticulin. Immunity 2001;14:303–13. [10] Quintana FJ, Cohen IR. Heat shock proteins as endogenous adjuvants in sterile and septic inflammation. J Immunol 2005;175:2777–82. [11] Hu SE, Zhu XR, Triggs JR, et al. Inflammation-induced, 30 UTR-dependent translational inhibition of HSP70 mRNA impairs intestinal homeostasis. Am J Physiol Gastrointest Liver Physiol 2009;296(5):G1003–11. [12] Liedel JL, Guo Y, Yu Y, et al. Mother’s milk-induced HSP70 expression preserves intestinal epithelial barrier function in an immature rat pup model. Pediatr Res 2011;69(5):395–400. [13] Ludwig D, Stahl M, Ibrahim ME, et al. Enhanced intestinal expression of heat shock protein 70 in patients with inflammatory bowel diseases. Dig Dis Sci 1999;44(7):1440–7. [14] Maynard CL, Elson CO, Hatton RD, et al. Reciprocal interactions of the intestinal microbiota and immune system. Nature 2012;489(7415):231–41. [15] Musch MW, Sugi K, Straus D, et al. Heat shock protein 72 protects against oxidant-induced injury of barrier function of human colonic epithelial Caco2/ bbe cells. Gastroenterology 1999;117(1):115–22. [16] Shroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-ASA therapy for mildly to moderately active ulcerative colitis. A randomized study. NEJM 1987;24213(26):1625–9. [17] Geboes K, Riddell R, Öst A, et al. A reproducible grading scale for histological assessment of inflammation in ulcerative colitis. Gut 2000;47:404–9. [18] Riddell RH, Goldman H, Ransohoff DF, et al. Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications. Hum Pathol 1983;14(11):931–68. [19] Suzuki M, Inoue Y, Tezuka T, et al. Local complications of the intestinal tract in patients with ulcerative colitis. Nihon Rinsho 1999;57(11):2527–31 (abstract). [20] Cosnes J, Gower-Rousseau C, Seksik P, et al. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology 2011;140:1785–94. [21] Feagins LA, Melton SD, Iqbal R, et al. Clinical implications of histologic abnormalities in colonic biopsy specimens from patients with ulcerative colitis in clinical remission. Inflamm Bowel Dis 2013 Jun;19(7):1477–82. [22] Schulz R, Moll UM. Targeting the heat shock protein 90: a rational way to inhibit macrophage migration inhibitory factor function in cancer. Curr Opin Oncol 2014;26(1):108–13. [23] Tao Y, Hart J, Lichtenstein L, et al. Inducible heat shock protein 70 prevents multifocal flat dysplastic lesions and invasive tumors in an inflammatory model of colon cancer. Carcinogenesis 2009;30(1):175–82.
Please cite this article in press as: Abou El Azm AR et al. Colonic mucosal expression of heat-shock proteins may have a potential prognostic value in ulcerative colitis. Arab J Gastroenterol (2015), http://dx.doi.org/10.1016/j.ajg.2015.02.005
