1
|
Wang H, Yang Y, Li T, Chang S, Zhu Y, Liu C. Drinking Water Temperature Impacts the Pathogenesis of DSS-Induced Ulcerative Colitis by Regulating Intestinal Barrier Function and Remodeling the Gut Microbiota Composition. FASEB J 2025; 39:e70645. [PMID: 40377203 DOI: 10.1096/fj.202500062r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 04/18/2025] [Accepted: 05/07/2025] [Indexed: 05/18/2025]
Abstract
Environmental factors, including poor dietary habits and unhealthy drinking patterns, contribute to ulcerative colitis (UC). While the relationship between diet-related malnutrition and UC has been extensively explored, the impact of drinking water temperature remains largely overlooked, prompting us to investigate its influence on UC pathogenesis and explore the underlying mechanisms. In the present study, we observed that, unlike external thermal and cold therapy, varying drinking water temperatures transiently altered the internal body temperature of the digestive tract. Specifically, chronic drinking of 0°C water had significant anti-inflammatory effects and preserved the integrity of the mucosal barrier in a colitis mouse model. Mechanistically, this temperature spectrum changed the composition of the gut microbiota from inflammation-prone (25°C drinking water) to a resting pattern similar to that of the negative control. Specifically, the abundances of Blautia and Parasutterella, two beneficial genera, were strongly increased in response to 0°C water, accompanied by elevated levels of short-chain fatty acids. In contrast, drinking 40°C water had opposite effects on all the examined parameters and generally aggravated the development of colitis. This study is the first to demonstrate how modifying the temperature of habitual drinking water can modulate colitis progression, providing a novel and noninvasive approach to UC management. Specifically, chronic consumption of 0°C water alleviated the severity of colitis, whereas 40°C water aggravated the disease. Therefore, by focusing on commonly consumed drinking water temperatures, our findings suggest that this simple intervention could be a safe, convenient, and effective therapeutic strategy.
Collapse
Affiliation(s)
- Huiting Wang
- Department of Endocrinology, Nanjing Drum Tower Hospital, China Pharmaceutical University, Nanjing, China
- State Key Laboratory of Natural Medicines and School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
- Jiangsu Provincial University Key Laboratory of Drug Discovery for Metabolic Inflammatory Diseases, China Pharmaceutical University, Nanjing, China
| | - Yiheng Yang
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tianyu Li
- Department of Endocrinology, Nanjing Drum Tower Hospital, China Pharmaceutical University, Nanjing, China
- State Key Laboratory of Natural Medicines and School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
- Jiangsu Provincial University Key Laboratory of Drug Discovery for Metabolic Inflammatory Diseases, China Pharmaceutical University, Nanjing, China
| | - Shengyu Chang
- Department of Endocrinology, Nanjing Drum Tower Hospital, China Pharmaceutical University, Nanjing, China
- State Key Laboratory of Natural Medicines and School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
- Jiangsu Provincial University Key Laboratory of Drug Discovery for Metabolic Inflammatory Diseases, China Pharmaceutical University, Nanjing, China
| | - Yao Zhu
- Department of Endocrinology, Nanjing Drum Tower Hospital, China Pharmaceutical University, Nanjing, China
- State Key Laboratory of Natural Medicines and School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
- Jiangsu Provincial University Key Laboratory of Drug Discovery for Metabolic Inflammatory Diseases, China Pharmaceutical University, Nanjing, China
| | - Chang Liu
- Department of Endocrinology, Nanjing Drum Tower Hospital, China Pharmaceutical University, Nanjing, China
- State Key Laboratory of Natural Medicines and School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
- Jiangsu Provincial University Key Laboratory of Drug Discovery for Metabolic Inflammatory Diseases, China Pharmaceutical University, Nanjing, China
| |
Collapse
|
2
|
Collins CB, Nguyen TT, Leddy RS, Alula KM, Yeckes AR, Strassheim D, Aherne CM, Luck ME, Karoor V, Jedlicka P, Pierce A, de Zoeten EF. Heat shock factor 1 drives regulatory T-cell induction to limit murine intestinal inflammation. Mucosal Immunol 2024; 17:94-110. [PMID: 37944754 PMCID: PMC10953693 DOI: 10.1016/j.mucimm.2023.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 10/13/2023] [Accepted: 11/02/2023] [Indexed: 11/12/2023]
Abstract
The heat shock response is a critical component of the inflammatory cascade that prevents misfolding of new proteins and regulates immune responses. Activation of clusters of differentiation (CD)4+ T cells causes an upregulation of heat shock transcription factor, heat shock factor 1 (HSF1). We hypothesized that HSF1 promotes a pro-regulatory phenotype during inflammation. To validate this hypothesis, we interrogated cell-specific HSF1 knockout mice and HSF1 transgenic mice using in vitro and in vivo techniques. We determined that while HSF1 expression was induced by anti-CD3 stimulation alone, the combination of anti-CD3 and transforming growth factor β, a vital cytokine for regulatory T cell (Treg) development, resulted in increased activating phosphorylation of HSF1, leading to increased nuclear translocation and binding to heat shock response elements. Using chromatin immunoprecipitation (ChIP), we demonstrate the direct binding of HSF1 to foxp3 in isolated murine CD4+ T cells, which in turn coincided with induction of FoxP3 expression. We defined that conditional knockout of HSF1 decreased development and function of Tregs and overexpression of HSF1 led to increased expression of FoxP3 along with enhanced Treg suppressive function. Adoptive transfer of CD45RBHigh CD4 colitogenic T cells along with HSF1 transgenic CD25+ Tregs prevented intestinal inflammation when wild-type Tregs did not. Finally, overexpression of HSF1 provided enhanced barrier function and protection from murine ileitis. This study demonstrates that HSF1 promotes Treg development and function and may represent both a crucial step in the development of induced regulatory T cells and an exciting target for the treatment of inflammatory diseases with a regulatory T-cell component. SIGNIFICANCE STATEMENT: The heat shock response (HSR) is a canonical stress response triggered by a multitude of stressors, including inflammation. Evidence supports the role of the HSR in regulating inflammation, yet there is a paucity of data on its influence in T cells specifically. Gut homeostasis reflects a balance between regulatory clusters of differentiation (CD)4+ T cells and pro-inflammatory T-helper (Th)17 cells. We show that upon activation within T cells, heat shock factor 1 (HSF1) translocates to the nucleus, and stimulates Treg-specific gene expression. HSF1 deficiency hinders Treg development and function and conversely, HSF1 overexpression enhances Treg development and function. While this work, focuses on HSF1 as a novel therapeutic target for intestinal inflammation, the findings have significance for a broad range of inflammatory conditions.
Collapse
Affiliation(s)
- Colm B Collins
- Mucosal Inflammation Program University of Colorado, Anschutz Medical Campus, Aurora, CO, USA; Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition University of Colorado, Anschutz Medical Campus, Aurora, CO, USA; Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Tom T Nguyen
- Mucosal Inflammation Program University of Colorado, Anschutz Medical Campus, Aurora, CO, USA; Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Robert S Leddy
- Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Kibrom M Alula
- Mucosal Inflammation Program University of Colorado, Anschutz Medical Campus, Aurora, CO, USA; Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Alyson R Yeckes
- Mucosal Inflammation Program University of Colorado, Anschutz Medical Campus, Aurora, CO, USA; Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Derek Strassheim
- Mucosal Inflammation Program University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Carol M Aherne
- Mucosal Inflammation Program University of Colorado, Anschutz Medical Campus, Aurora, CO, USA; Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Marisa E Luck
- Mucosal Inflammation Program University of Colorado, Anschutz Medical Campus, Aurora, CO, USA; Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Vijaya Karoor
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Paul Jedlicka
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | | | - Edwin F de Zoeten
- Mucosal Inflammation Program University of Colorado, Anschutz Medical Campus, Aurora, CO, USA; Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
| |
Collapse
|
3
|
Kim SW, Lee JY, Lee HC, Ahn JB, Kim JH, Park IS, Cheon JH, Kim DH. Downregulation of Heat Shock Protein 72 Contributes to Fibrostenosis in Crohn's Disease. Gut Liver 2023; 17:905-915. [PMID: 36814356 PMCID: PMC10651382 DOI: 10.5009/gnl220308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 10/21/2022] [Accepted: 11/29/2022] [Indexed: 02/24/2023] Open
Abstract
Background/Aims Crohn's disease (CD) with recurrent inflammation can cause intestinal fibrostenosis due to dysregulated deposition of extracellular matrix. However, little is known about the pathogenesis of fibrostenosis. Here, we performed a differential proteomic analysis between normal, inflamed, and fibrostenotic specimens of patients with CD and investigated the roles of the candidate proteins in myofibroblast activation and fibrosis. Methods We performed two-dimensional difference gel electrophoresis and identified candidate proteins using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and orbitrap liquid chromatography-mass spectrometry. We also verified the levels of candidate proteins in clinical specimens and examined their effects on 18Co myofibroblasts and Caco-2 intestinal epithelial cells. Results We identified five of 30 proteins (HSP72, HSPA5, KRT8, PEPCK-M, and FABP6) differentially expressed in fibrostenotic CD. Among these proteins, the knockdown of heat shock protein 72 (HSP72) promoted the activation and wound healing of myofibroblasts. Moreover, knockdown of HSP72 induced the epithelial-mesenchymal transition of intestinal epithelial cells by reducing E-cadherin and inducing fibronectin and α-smooth muscle actin, which contribute to fibrosis. Conclusions HSP72 is an important mediator that regulates myofibroblasts and epithelial-mesenchymal transition in fibrosis of CD, suggesting that HSP72 can serve as a target for antifibrotic therapy.
Collapse
Affiliation(s)
- Seung Won Kim
- Department of Internal Medicine and Institute of Gastroenterology, Graduate School of Medical Science, Brain Korea 21 Project, Seoul, Korea
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Jae-Young Lee
- Department of Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Han Cheol Lee
- Department of Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Jae Bum Ahn
- Department of Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Ji Hyung Kim
- Department of Internal Medicine and Institute of Gastroenterology, Graduate School of Medical Science, Brain Korea 21 Project, Seoul, Korea
| | - I Seul Park
- Department of Internal Medicine and Institute of Gastroenterology, Graduate School of Medical Science, Brain Korea 21 Project, Seoul, Korea
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Graduate School of Medical Science, Brain Korea 21 Project, Seoul, Korea
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Duk Hwan Kim
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| |
Collapse
|
4
|
Hoter A, Naim HY. The Functions and Therapeutic Potential of Heat Shock Proteins in Inflammatory Bowel Disease-An Update. Int J Mol Sci 2019; 20:ijms20215331. [PMID: 31717769 PMCID: PMC6862201 DOI: 10.3390/ijms20215331] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 10/24/2019] [Accepted: 10/25/2019] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a multifactorial human intestinal disease that arises from numerous, yet incompletely defined, factors. Two main forms, Crohn's disease (CD) and ulcerative colitis (UC), lead to a chronic pathological form. Heat shock proteins (HSPs) are stress-responsive molecules involved in various pathophysiological processes. Several lines of evidence link the expression of HSPs to the development and prognosis of IBD. HSP90, HSP70 and HSP60 have been reported to contribute to IBD in different aspects. Moreover, induction and/or targeted inhibition of specific HSPs have been suggested to ameliorate the disease consequences. In the present review, we shed the light on the role of HSPs in IBD and their targeting to prevent further disease progression.
Collapse
Affiliation(s)
- Abdullah Hoter
- Department of Biochemistry and Chemistry of Nutrition, Faculty of Veterinary Medicine, Cairo University, Giza 12211, Egypt or
- Department of Physiological Chemistry, University of Veterinary Medicine Hannover, 30559 Hannover, Germany
| | - Hassan Y. Naim
- Department of Physiological Chemistry, University of Veterinary Medicine Hannover, 30559 Hannover, Germany
- Correspondence: ; Tel.: +49-511-953-8780; Fax: +49-511-953-8585
| |
Collapse
|
5
|
Regeling A, Imhann F, Volders HH, Blokzijl T, Bloks VW, Weersma RK, Dijkstra G, Faber KN. HSPA6 is an ulcerative colitis susceptibility factor that is induced by cigarette smoke and protects intestinal epithelial cells by stabilizing anti-apoptotic Bcl-XL. Biochim Biophys Acta Mol Basis Dis 2016; 1862:788-796. [DOI: 10.1016/j.bbadis.2016.01.020] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Revised: 01/15/2016] [Accepted: 01/21/2016] [Indexed: 12/20/2022]
|
6
|
Collins CB, Aherne CM, Yeckes A, Pound K, Eltzschig HK, Jedlicka P, de Zoeten EF. Inhibition of N-terminal ATPase on HSP90 attenuates colitis through enhanced Treg function. Mucosal Immunol 2013; 6:960-71. [PMID: 23321985 PMCID: PMC3748235 DOI: 10.1038/mi.2012.134] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2012] [Accepted: 11/26/2012] [Indexed: 02/04/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory condition thought to reflect a failure of the enteral immune system to adequately regulate itself. Inflammatory stress drives upregulation of heat-shock proteins (HSPs), including the pro-inflammatory chaperone, HSP90. This protein sequesters the transcription factor, heat-shock factor 1 (HSF1) in the cytoplasm preventing transcription of a number of anti-inflammatory proteins. We hypothesized that inhibition of HSP90 would exert an anti-inflammatory effect and thereby attenuate intestinal inflammation in murine models of IBD. Inhibition of HSP90 with 17-allylaminogeldanamycin (17-AAG) reduced inflammation in acute dextran sodium sulfate and chronic CD45RB(High) colitis models coinciding with increased interleukin (IL)-10 production in the colon. Regulatory T cells (Tregs) from mice treated with 17-AAG demonstrated significantly greater suppressive capacity in vitro abolished in HSF1-/- or IL-10-/- cells. Finally, Tregs treated with 17-AAG exhibited increased nuclear localization of HSF1 with resultant upregulation of HSF1 response genes, including HSP70, HSP90 and IL-10.
Collapse
Affiliation(s)
- Colm B. Collins
- Mucosal Inflammation Program, University of Colorado School of Medicine, Department of Pediatrics, Children's Hospital Colorado, Digestive Health Institute, Colorado 80045
| | - Carol M. Aherne
- University of Colorado School of Medicine, Department of Anesthesiology, Colorado 80045
| | - Alyson Yeckes
- Mucosal Inflammation Program, University of Colorado School of Medicine, Department of Pediatrics, Children's Hospital Colorado, Digestive Health Institute, Colorado 80045
| | - Kayla Pound
- Mucosal Inflammation Program, University of Colorado School of Medicine, Department of Pediatrics, Children's Hospital Colorado, Digestive Health Institute, Colorado 80045
| | - Holger K. Eltzschig
- University of Colorado School of Medicine, Department of Anesthesiology, Colorado 80045
| | - Paul Jedlicka
- University of Colorado School of Medicine, Department of Pathology, Colorado 80045
| | - Edwin F. de Zoeten
- Mucosal Inflammation Program, University of Colorado School of Medicine, Department of Pediatrics, Children's Hospital Colorado, Digestive Health Institute, Colorado 80045
| |
Collapse
|
7
|
Gut microbiota imbalance and chaperoning system malfunction are central to ulcerative colitis pathogenesis and can be counteracted with specifically designed probiotics: a working hypothesis. Med Microbiol Immunol 2013; 202:393-406. [PMID: 23864544 DOI: 10.1007/s00430-013-0305-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2013] [Accepted: 06/29/2013] [Indexed: 12/19/2022]
Abstract
In this work, we propose that for further studies of the physiopathology and treatment for inflammatory bowel diseases, an integral view of the conditions, including the triad of microbiota-heat shock proteins (HSPs)-probiotics, ought to be considered. Microbiota is the complex microbial flora that resides in the gut, affecting not only gut functions but also the health status of the whole body. Alteration in the microbiota's composition has been implicated in a variety of pathological conditions (e.g., ulcerative colitis, UC), involving both gut and extra-intestinal tissues and organs. Some of these pathologies are also associated with an altered expression of HSPs (chaperones) and this is the reason why they may be considered chaperonopathies. Probiotics, which are live microorganisms able to restore the correct, healthy equilibrium of microbiota composition, can ameliorate symptoms in patients suffering from UC and modulate expression levels of HSPs. However, currently probiotic therapy follows ex-adiuvantibus criteria, i.e., treatments with beneficial effects but whose mechanism of action is unknown, which should be changed so the probiotics needed in each case are predetermined on the basis of the patient's microbiota. Consequently, efforts are necessary to develop diagnostic tools for elucidating levels and distribution of HSPs and the microbiota composition (microbiota fingerprint) of each subject and, thus, guide specific probiotic therapy, tailored to meet the needs of the patient. Microbiota fingerprinting ought to include molecular biology techniques for sequencing highly conserved DNA, e.g., genes encoding 16S RNA, for species identification and, in addition, quantification of each relevant microbe.
Collapse
|
8
|
Kim EK, Lee KY, Lee HJ, Lee JA, Choi CW, Kim HS, Kim BI, Choi JH. Heat shock pretreatment reduces intestinal injury in a neonatal rat model of early necrotizing enterocolitis. Neonatology 2013; 103:1-6. [PMID: 22948204 DOI: 10.1159/000339179] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2012] [Accepted: 04/30/2012] [Indexed: 12/20/2022]
Abstract
BACKGROUND Increased pro-inflammatory cytokines are suggested in the pathogenesis of necrotizing enterocolitis (NEC). The transcription factor, nuclear factor-ĸB (NF-ĸB), is a central regulator of inflammatory and immune responses, and recent rodent NEC models have shown that NF-ĸB may have a critical role in the disease processes that underlie NEC. Heat shock proteins have important functions in response to stress-related events in a variety of systems, including digestive organs. OBJECTIVES We investigated whether heat shock pretreatment protects intestinal epithelial damage in the early NEC rat model. METHODS We generated human NEC-like lesions in neonatal rat ileum by administering oral endotoxin (10 mg/kg), intermittent 8% hypoxia, and hypertonic formula. Heat shock was administered by raising the chamber temperature to 42°C for 20 min, 3 h prior to endotoxin ingestion. RESULTS Heat shock pretreatment increased the expression of HSP70 in the ileal tissue and attenuated histological severity of early experimental NEC. NF-ĸB was activated in the ileal tissue of the NEC group and this activation was attenuated by heat shock pretreatment, which was determined by electrophoretic mobility shift assay and Western blot analysis of p50 in subcellular fractionated samples. CONCLUSIONS Heat shock pretreatment reduced the incidence and severity of early experimental NEC in rats. A possible mechanism underlying this protective effect includes inhibition of NF-ĸB activation through increased HSP70 expression.
Collapse
Affiliation(s)
- Ee-Kyung Kim
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | | | | | | | | | | | | | | |
Collapse
|
9
|
Tomasello G, Bellavia M, Damiano G, Gioviale MC, Lo Monte AI. Possible relation between gut microflora composition and oncogenic risk. ACTA ACUST UNITED AC 2012. [DOI: 10.1097/mrm.0b013e328353f49c] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
|
10
|
Ahmed K, Furusawa Y, Tabuchi Y, Emam HF, Piao JL, Hassan MA, Yamamoto T, Kondo T, Kadowaki M. Chemical inducers of heat shock proteins derived from medicinal plants and cytoprotective genes response. Int J Hyperthermia 2012; 28:1-8. [PMID: 22235779 DOI: 10.3109/02656736.2011.627408] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Environmental stress induces damage that activates an adaptive response in any organism. The cellular stress response is based on the induction of cytoprotective proteins, the so-called stress or heat shock proteins (HSPs). HSPs are known to function as molecular chaperones which are involved in the therapeutic approach of many diseases. Therefore in the current study we searched nontoxic chaperone inducers in chemical compounds isolated from medicinal plants. Screening of 80 compounds for their Hsp70-inducing activity in human lymphoma U937 cells was performed by western blotting. Five compounds showed significant Hsp70 up-regulation among them shikonin was most potent. Shikonin was able to induce Hsp70 at 0.1 µM after 3 h without activation of heat shock transcription factor 1 (HSF-1). It also induces significant reactive oxygen species generation. The expression level of genes responsive to shikonin was studied using global-scale microarrays and computational gene expression analysis tools. Significant increase in the nuclear factor erythroid 2-related factor 2 (Nrf2, NFEL2L2) -mediated oxidative stress response was observed that leads to the activation of HSP. The results of gene chip analysis were further confirmed by real-time qPCR assay. In short, the detailed mechanisms of Hsp70 induction by shikonin is not fully understood, Nrf2 and its target genes might be involved in the Hsp70 up-regulation in U937 cells.
Collapse
Affiliation(s)
- Kanwal Ahmed
- Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, Toyama, Japan
| | | | | | | | | | | | | | | | | |
Collapse
|
11
|
Park SC, Lim JY, Jeen YT, Keum B, Seo YS, Kim YS, Lee SJ, Lee HS, Chun HJ, Um SH, Kim CD, Ryu HS, Sul D, Oh E. Ethanol-induced DNA damage and repair-related molecules in human intestinal epithelial Caco-2 cells. Mol Med Rep 2012; 5:1027-32. [PMID: 22246134 PMCID: PMC3493059 DOI: 10.3892/mmr.2012.754] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2011] [Accepted: 01/03/2012] [Indexed: 01/25/2023] Open
Abstract
The acute administration of ethanol to intestinal epithelial cells causes increased intestinal permeability and the translocation of endotoxins. The changes caused by ethanol in intestinal cells may be related to oxidative stress and DNA damage. However, DNA damage and repair-related molecules which act against stresses, including ethanol, have not been fully investigated in intestinal cells. Heat shock proteins (Hsps) are involved in the recovery and protection from cell damage and may be associated with DNA repair. Therefore, the aim of our study was to investigate cytotoxicity, DNA damage and the expression of DNA repair-related molecules, antioxidant proteins and Hsps in intestinal cells exposed to ethanol. Human intestinal Caco-2 cells were incubated with 1-8% ethanol for 1 h. Cell viability and DNA damage were determined using the MTT and comet assays, respectively. We measured DNA repair-related molecules, including DNA polymerase β, apurinic/apyrimidinic endonuclease/redox factor-1 (APE/Ref-1), growth arrest and DNA damage 45α (GADD45α) and proliferating cell nuclear antigen (PCNA), in Caco-2 cells using western blot analysis. We also measured glutathione peroxidase-1 (GPx-1), peroxiredoxin-1 (PRX-1), superoxide dismutase-2 (SOD-2), Hsp10, Hsp27, Hsp60, heat shock cognate (Hsc)70, Hsp70 and Hsp90. The viability of the Caco-2 cells exposed to ethanol decreased at concentrations ≥ 7% (P<0.05). The Olive tail moment, indicating DNA damage, increased dose dependently in ≥ 3% ethanol (P<0.05). Among the DNA repair proteins, the expression of PCNA and APE/Ref-1 increased significantly at 1% ethanol. Antioxidant enzymes, including GPx-1, PRX-1 and SOD-2, had an increased expression at 1% ethanol. Hsp10, Hsp27 and Hsp70 expression also increased significantly at 1% ethanol. In conclusion, the expression of DNA repair molecules, antioxidants and Hsps increased in intestinal Caco-2 cells exposed to low concentrations of ethanol. In particular, PCNA, APE/Ref-1, Hsp10, Hsp27 and Hsp70 were sensitive to low ethanol concentrations, indicating that they may be useful in evaluating the DNA repair and cytoprotective effects of the drug against stress in intestinal cells.
Collapse
Affiliation(s)
- Sung Chul Park
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Republic of Korea
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
12
|
Dietary heme adversely affects experimental colitis in rats, despite heat-shock protein induction. Nutrition 2011; 27:590-7. [DOI: 10.1016/j.nut.2010.05.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2010] [Revised: 03/22/2010] [Accepted: 05/03/2010] [Indexed: 12/22/2022]
|
13
|
Asai M, Kawashima D, Katagiri K, Takeuchi R, Tohnai G, Ohtsuka K. Protective effect of a molecular chaperone inducer, paeoniflorin, on the HCl- and ethanol-triggered gastric mucosal injury. Life Sci 2011; 88:350-7. [DOI: 10.1016/j.lfs.2010.12.014] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2010] [Revised: 11/18/2010] [Accepted: 12/06/2010] [Indexed: 01/20/2023]
|
14
|
Lallès JP, David JC. Fasting and refeeding modulate the expression of stress proteins along the gastrointestinal tract of weaned pigs. J Anim Physiol Anim Nutr (Berl) 2010; 95:478-88. [PMID: 21091542 DOI: 10.1111/j.1439-0396.2010.01075.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
The gastrointestinal tract (GIT) of young mammals is submitted to aggressions early in life and GIT stress proteins are up-regulated in pigs following weaning. We hypothesized that transient food deprivation may contribute to these changes. Therefore, the effects of fasting and refeeding on GIT stress proteins in weaned pigs were investigated. A complete block experimental design with three groups of five pigs each was set up with the following treatments: A - food offered, B - fasted for 1.5 days, C - fasted for 1.5 days and then re-fed for 2.5 days. After slaughter, the GIT was removed, weighed and sampled. Intestinal villi and crypts were measured and alkaline phosphatase activity was determined. GIT tissue stress protein concentrations were measured by Western blotting. Fasting led to intestinal mucosa and villous-crypt atrophy (p < 0.01) and reduced mucosal alkaline phosphatase total activity in the proximal small intestine (p < 0.05). Heat shock proteins HSP 27 and HSP 90 (but not HSP 70) and neuronal NO synthase (nNOS) increased (p < 0.01) in the stomach, mid-intestine and proximal colon with fasting. Inducible NOS (iNOS) did so in the stomach (p < 0.001). Refeeding partially or totally restored GIT characteristics and stress protein concentrations, except for gastric HSP 90 and iNOS. Significant correlations (p < 0.05 to p < 0.0001) were found among stress proteins, between nNOS and digesta weight, between HSP 27 or HSP 90 and intestinal mucosa weight, and between intestinal or colonic HSP or nNOS and alkaline phosphatase. In conclusion, fasting and refeeding modulate GIT HSP proteins and nNOS in pigs following weaning. Changes in digesta and intestinal mucosa weights and alkaline phosphatase activity may be involved in the modulation of stress proteins along the GIT.
Collapse
Affiliation(s)
- J P Lallès
- Institut National de la Recherche Agronomique, Saint-Gilles, France.
| | | |
Collapse
|
15
|
Rodolico V, Tomasello G, Zerilli M, Martorana A, Pitruzzella A, Marino Gammazza A, David S, Zummo G, Damiani P, Accomando S, Conway de Macario E, Macario AJL, Cappello F. Hsp60 and Hsp10 increase in colon mucosa of Crohn’s disease and ulcerative colitis. Cell Stress Chaperones 2010; 15:877-84. [PMID: 20390473 PMCID: PMC3024080 DOI: 10.1007/s12192-010-0196-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2010] [Revised: 03/25/2010] [Accepted: 03/26/2010] [Indexed: 12/13/2022] Open
Abstract
The purpose of this work was to determine in colon mucosa of Crohn’s disease (CD) and ulcerative colitis (UC) in relapse: a) the levels of the chaperonins Hsp60 and Hsp10; b) the quantity of inflammatory cells; and c) if the levels of chaperonins parallel those of inflammation cells. Twenty cases of CD and UC and twenty normal controls (NC) were studied using immunohistochemistry, Western blotting and immunofluorescence. Immunohistochemically, Hsp60 and Hsp10 were increased in both inflammatory bowel diseases (IBD) compared to NC. These results were confirmed by Western blotting. Hsp60 and Hsp10 occurred in the cytoplasm of epithelial cells in CD and UC but not in NC. Hsp60 and Hsp10 co-localised to epithelial cells of mucosal glands but not always in connective tissue cells of lamina propria, where only Hsp60 or, less often, Hsp10 was found. Cells typical of inflammation were significantly more abundant in CD and UC than in NC. Since chaperonins are key factors in the activation of the immune system leading to inflammation, we propose that they play a central role in the pathogenesis of the two diseases, which, consequently, ought to be studied as chaperonopathies.
Collapse
Affiliation(s)
- Vito Rodolico
- Dipartimento di Patologia Umana, Università degli Studi di Palermo, Palermo, Italy
| | - Giovanni Tomasello
- Dipartimento di Chirurgia Generale, d’Urgenza e Trapianti d’Organo, Università degli Studi di Palermo, Palermo, Italy
| | - Monica Zerilli
- Dipartimento di Patologia Umana, Università degli Studi di Palermo, Palermo, Italy
| | - Anna Martorana
- Dipartimento di Patologia Umana, Università degli Studi di Palermo, Palermo, Italy
| | - Alessandro Pitruzzella
- Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche, Università degli Studi di Palermo, Sezione di Anatomia Umana, via del Vespro 129, 90127 Palermo, Italy
| | - Antonella Marino Gammazza
- Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche, Università degli Studi di Palermo, Sezione di Anatomia Umana, via del Vespro 129, 90127 Palermo, Italy
| | - Sabrina David
- Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche, Università degli Studi di Palermo, Sezione di Anatomia Umana, via del Vespro 129, 90127 Palermo, Italy
| | - Giovanni Zummo
- Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche, Università degli Studi di Palermo, Sezione di Anatomia Umana, via del Vespro 129, 90127 Palermo, Italy
| | - Provvidenza Damiani
- Dipartimento di Medicina Interna, Malattie Cardiovascolari e Nefrourologiche, Università degli Studi di Palermo, Palermo, Italy
| | - Salvatore Accomando
- Dipartimento Materno-Infantile, Università degli Studi di Palermo, Palermo, Italy
| | | | | | - Francesco Cappello
- Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche, Università degli Studi di Palermo, Sezione di Anatomia Umana, via del Vespro 129, 90127 Palermo, Italy
- Istituto Euro-Mediterraneo di Scienza e Tecnologia (IEMEST), Palermo, Italy
| |
Collapse
|
16
|
Takahashi T, Otaka M, Odashima M, Tamaki K, Takada M, Izumi Y, Shibuya T, Sakamoto N, Itoh H, Watanabe S. Correlation of heat shock protein expression to gender difference in development of stress-induced gastric mucosal injury in rats. J Clin Biochem Nutr 2010; 47:64-73. [PMID: 20664733 PMCID: PMC2901766 DOI: 10.3164/jcbn.10-32] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2010] [Accepted: 03/19/2010] [Indexed: 12/21/2022] Open
Abstract
Recent studies have indicated that heat shock proteins (HSPs), which function as molecular chaperones, play important roles in cellular responses to stress-related events. However, the gender difference in the expression of HSP in the gastric mucosa remains unclear. In order to understand the mechanism of gender difference in the prevalence or severity of gastric mucosal lesions, the expression level of HSP and the correlation of estrogen to HSP induction in the gastric mucosa were evaluated in this study. The basal expression levels of HSP60 and HSP90 in the gastric mucosa were significantly higher in females than those in males. The gastric ulcer index was significantly higher in male rats compared to female rats observed after 12 h water immersion stress exposure. At this time point, the expression levels of HSP60 and HSP90 in the gastric mucosa were significantly higher in females than those in males. An estrogen-treatment significantly induced the expression of HSP60, HSP70 and HSP90 in the gastric mucosa. Inversely, an ovariectomy dramatically reduced the expression of HSP60, HSP70 and HSP90 in the gastric mucosa. Our results suggested that estrogen might play an important role in gastric mucosal protection with the induction of gastric mucosal HSPs.
Collapse
Affiliation(s)
- Taiji Takahashi
- Department of Gastroenterology, Juntendo University School of Medicine, Bunkyo-Ku, Tokyo 113-8421, Japan
| | | | | | | | | | | | | | | | | | | |
Collapse
|
17
|
Takada M, Otaka M, Takahashi T, Izumi Y, Tamaki K, Shibuya T, Sakamoto N, Osada T, Yamamoto S, Ishida R, Odashima M, Itoh H, Watanabe S. Overexpression of a 60-kDa heat shock protein enhances cytoprotective function of small intestinal epithelial cells. Life Sci 2010; 86:499-504. [PMID: 20159025 DOI: 10.1016/j.lfs.2010.02.010] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2009] [Revised: 01/27/2010] [Accepted: 02/02/2010] [Indexed: 12/22/2022]
Abstract
AIMS With the advancement of small intestinal (double balloon and capsule) endoscopy technology, incidence of small intestinal lesion caused by nonsteroidal anti-inflammatory drugs (NSAIDs) has been known to be high. However, therapy for small intestinal mucosal lesion has not yet been developed. Previous studies have shown that heat shock proteins (HSPs) are involved in cytoprotection mediated by their function as a molecular chaperone. In this study, we examined the effect of HSP60 or HSP70 overexpression on hydrogen peroxide-induced (H2O2) or indomethacin-induced cell damage in the small intestinal epithelial cells. MAIN METHODS cDNA of human HSP60 or HSP70 was transfected to rat small intestinal (IEC-6) cells, and HSP60- or HSP70-overexpressing cells were cloned. IEC-6 cells transfected with vector only were used as control cells. These cells were treated with H2O2 (0-0.14mM) or indomethacin (0-2.5mM). The cell viability was determined by MTT-assay. Cell necrosis was evaluated by LDH-release assay. Further, apoptosis was evaluated by caspases-3/7 activity and TUNEL assay. KEY FINDINGS Cell viability after H2O2 or indomethacin treatment was significantly higher in HSP60-overexpressing cells compared with that in control cells and HSP60-overexpressing cells. Apoptotic cells were also reduced in HSP60-overexpressing. CONCLUSION These results indicate that HSP60 plays an important role in protecting small intestinal mucosal cells from H2O2-induced or indomethacin-induced cell injury. HSP70-overexpressing cells did not show anti-apoptotic ability. SIGNIFICANCE These findings possibly suggest that function of each HSP is different in the small intestine. Therefore, for the therapy of small intestinal mucosal lesion, HSP60-induction therapy could be a new therapeutic strategy.
Collapse
Affiliation(s)
- Makiko Takada
- Department of Gastroenterology, Juntendo University School of Medicine, Japan.
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
18
|
Otaka M, Odashima M, Tamaki K, Watanabe S. Expression and function of stress (heat shock) proteins in gastrointestinal tract. Int J Hyperthermia 2009; 25:634-40. [DOI: 10.3109/02656730903315815] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
|
19
|
Specific induction of a 72-kDa heat shock protein protects esophageal mucosa from reflux esophagitis. Life Sci 2009; 84:517-22. [DOI: 10.1016/j.lfs.2009.01.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2008] [Revised: 12/19/2008] [Accepted: 01/26/2009] [Indexed: 11/21/2022]
|
20
|
Tanaka KI, Tsutsumi S, Arai Y, Hoshino T, Suzuki K, Takaki E, Ito T, Takeuchi K, Nakai A, Mizushima T. Genetic evidence for a protective role of heat shock factor 1 against irritant-induced gastric lesions. Mol Pharmacol 2007; 71:985-93. [PMID: 17189318 DOI: 10.1124/mol.106.033282] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Gastric lesions result from an imbalance between aggressive and defensive factors. Indirect lines of evidence suggest that heat shock proteins (HSPs) induced by various aggressive factors provide a major protective mechanism. In this study, we compared gastric ulcerogenic response in wild-type mice and in those lacking heat shock factor 1 (HSF1), a transcription factor for hsp genes. The severity of gastric lesions induced by ethanol or hydrochloric acid was worsened in HSF1-null mice. Immunoblotting, real-time reverse transcription-polymerase chain reaction, immunohistochemical analysis, and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay revealed that the ethanol administration up-regulated gastric mucosal HSPs, in particular HSP70, in an HSF1-dependent manner, and more apoptotic cells were observed in the gastric mucosa of HSF1-null mice than in wild-type mice. In contrast, other parameters governing the gastric ulcerogenic response, including gastric acid secretion, gastric mucosal blood flow, and prostaglandin E(2) levels, were not significantly affected by the absence of the hsf1 gene. Geranylgeranylacetone (GGA), a clinically used antiulcer drug with HSP-inducing activity, suppressed ethanol-induced gastric lesions in wild-type mice but not in heat shock factor 1 (HSF1)-null mice. The results suggest that the aggravation of irritant-induced gastric lesions in HSF1-null mice is due to their inability to up-regulate HSPs, leading to apoptosis. It is also suggested that the HSP-inducing activity of GGA contributes to the drug's antiulcer activity. This study provides direct genetic evidence that HSPs, after their HSF1-dependent up-regulation, confer gastric protection against the irritant-induced lesions.
Collapse
Affiliation(s)
- Ken-Ichiro Tanaka
- Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan
| | | | | | | | | | | | | | | | | | | |
Collapse
|
21
|
Odashima M, Otaka M, Jin M, Wada I, Horikawa Y, Matsuhashi T, Ohba R, Hatakeyama N, Oyake J, Watanabe S. Zinc l-carnosine protects colonic mucosal injury through induction of heat shock protein 72 and suppression of NF-κB activation. Life Sci 2006; 79:2245-50. [PMID: 16949620 DOI: 10.1016/j.lfs.2006.07.032] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2006] [Revised: 07/02/2006] [Accepted: 07/22/2006] [Indexed: 10/24/2022]
Abstract
In this study, we investigated the effects of zinc L-carnosine, an anti-ulcer drug, on acetic acid-induced colonic mucosal injury and the correlation of these effects with expression of 72-kDa heat shock proteins (HSP72) and nuclear factor kappa B (NF-kappaB) activation in rat colonic mucosa in vivo. After intrarectal administration of zinc L-carnosine, the rats received intrarectal infusion of 5% acetic acid (1 ml). The colonic mucosal damage was evaluated by macroscopic assessments 24 h after the intrarectal infusion of acetic acid. Expression of HSP72 in rat colonic mucosa was evaluated by Western blot analysis before and after zinc L-carnosine administration. NF-kappaB activation was evaluated by electrophoretic mobility shift assays (EMSA). Zinc L-carnosine inhibited visible damage in rat colonic mucosa by acetic acid. Expression of HSP72 was significantly increased at 6 h after zinc L-carnosine administration. Furthermore, NF-kappaB activation in colonic mucosa was suppressed 6 h after zinc L-carnosine treatment. These results suggested that zinc L-carnosine protects the colonic mucosa against acetic acid by induction of HSP72 and suppression of NF-kappaB activation and zinc L-carnosine may be a novel therapeutic agent for the therapy of inflammatory bowel disease.
Collapse
Affiliation(s)
- Masaru Odashima
- Department of Gastroenterology, Akita University School of Medicine, 1-1-1, Hondo, Akita City, Akita 010-8543, Japan.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
22
|
Ohkawara T, Nishihira J, Nagashima R, Takeda H, Asaka M. Polaprezinc protects human colon cells from oxidative injury induced by hydrogen peroxide: Relevant to cytoprotective heat shock proteins. World J Gastroenterol 2006; 12:6178-81. [PMID: 17036391 PMCID: PMC4088113 DOI: 10.3748/wjg.v12.i38.6178] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of polaprezinc on cellular damage induced by hydrogen peroxide (H2O2) in human colon CaCo2 cells.
METHODS: CaCo2 cells were treated with polaprezinc (10-100 μmol/L) for 6 h. After polaprezinc treatment, the cells were incubated with H2O2 (20 μmol/L) for 1 h. Cell viability was measured by MTT assay. Western blot analysis for heat shock protein (HSP) 27 and HSP72 in the cells was performed. Moreover, cells were pretreated with quercetin (200 μmol/L), an inhibitor of HSP synthesis, 2 h before polaprezinc treatment, and cell viability and the expression of HSP27 and 72 were assessed in these cells.
RESULTS: Polaprezinc significantly protected CaCo2 cells from cell damage induced by H2O2, and up-regulated the expressions of HSP27 and HSP72 in the cells (10, 30 and 100 μmol/L of polaprezinc; 35.0% ± 7.7%, 58.3% ± 14.6% and 64.2% ± 8.2%, respectively. P < 0.01 versus polaprezinc-nontreated cells; 6.0% ± 4.4%). Quercetin inhibited the up-regulation of HSP27 and HSP72 by polaprezinc and diminished the protective effect of polaprezinc against H2O2-caused injury in the cells.
CONCLUSION: Polaprezinc is a useful therapeutic agent for treatment of colitis and its effects depend on the function of cytoprotective HSP in colon.
Collapse
Affiliation(s)
- Tatsuya Ohkawara
- Department of Gastroenterology and Hematology, Hokkaido University Graduate School of Medicine, Kita15, Nishi7, Kita-ku, 060-8678 Sapporo, Japan.
| | | | | | | | | |
Collapse
|
23
|
Wada I, Otaka M, Jin M, Odashima M, Komatsu K, Konishi N, Matsuhashi T, Horikawa Y, Ohba R, Itoh H, Watanabe S. Expression of HSP72 in the gastric mucosa is regulated by gastric acid in rats-correlation of HSP72 expression with mucosal protection. Biochem Biophys Res Commun 2006; 349:611-8. [PMID: 16945336 DOI: 10.1016/j.bbrc.2006.08.088] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2006] [Accepted: 08/16/2006] [Indexed: 11/21/2022]
Abstract
BACKGROUND AND AIM The real mechanism of adaptive cytoprotection in the gastric mucosa is not well established. In the present study, we investigated the effect of acid suppressing agents on a 72-kDa heat shock protein (HSP72) expression, which is known as endogenous cytoprotective factor, in the gastric mucosa. Also, the association of gastric mucosal protective function against HCl-challenge was compared between HSP72-induced and -reduced group. MATERIALS AND METHODS Expression of HSP72 was measured by Western blotting in the gastric mucosa before and after administration of famotidine or omeprazole. The gastric mucosal protective function against 0.6 N HCl was compared between control group and HSP72-reduced group. Also, the effect of increased expression of gastric HSP72 by additional administration of zinc sulfate or zinc L-carnosine, which is known as HSP72-inducer, on mucosal protective function was studied. RESULTS HSP72 expression in the gastric mucosa was reduced by acid suppressing agents. The lowest expression level of HSP72 was observed 12 h (famotidine, H2-receptor antagonist) or 48 h (omeprazole, proton pump inhibitor) after administration. The gastric mucosal protective ability against 0.6 N HCl was also reduced when HSP72 expression was decreased by famotidine or omeprazole. This phenomenon was reversed by HSP72 induction by additional administration of zinc derivatives. CONCLUSION Our results might indicate that the expression of HSP72 in the gastric mucosa is physiologically regulated by gastric acid, and that HSP72 induction could be important in view of mucosal protection especially when HSP72 expression is reduced by administration of acid suppressing agents such as proton pump inhibitor or H2 receptor antagonist.
Collapse
Affiliation(s)
- Isao Wada
- Department of Internal Medicine and Gastroenterology, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
24
|
Otaka M, Odashima M, Watanabe S. Role of heat shock proteins (molecular chaperones) in intestinal mucosal protection. Biochem Biophys Res Commun 2006; 348:1-5. [PMID: 16875664 DOI: 10.1016/j.bbrc.2006.07.028] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2006] [Accepted: 07/10/2006] [Indexed: 02/07/2023]
Abstract
Most studies into the pathogenesis of inflammatory bowel diseases (IBD) have primarily focused on the cytotoxic agents and processes involved in producing mucosal injury, including the immune system. However, less consideration has been given to the inherent mechanisms of cytoprotection and cellular repair in the intestinal mucosa. This review will focus on intestinal mucosal protection against cytotoxic agents and cellular stress mainly from the viewpoint of expression and function of heat shock proteins, in their role of "molecular chaperones," as internal cytoprotectants. Elucidation of such stress-responses in the intestinal mucosa may provide a better understanding of the mechanisms of cytoprotection and cellular repair, and present new strategies for IBD therapy.
Collapse
Affiliation(s)
- Michiro Otaka
- Department of Internal Medicine and Gastroenterology, Akita University School of Medicine, Akita 010-8543, Japan.
| | | | | |
Collapse
|
25
|
OTAKA M, MATSUHASHI T, ODASHIMA M, ITOH H, JIN M, WADA I, KOMATSU K, HORIKAWA Y, OHBA R, OYAKE J, HATAKEYAMA N, WATANABE S. Enhancement of cytoprotective ability and cell restoration in 70-kDa heat shock protein gene-transfected rat gastric mucosal cells. ACTA ACUST UNITED AC 2006. [DOI: 10.1111/j.1746-6342.2006.00056.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
|
26
|
Ohkawara T, Takeda H, Kato K, Miyashita K, Kato M, Iwanaga T, Asaka M. Polaprezinc (N-(3-aminopropionyl)-L-histidinato zinc) ameliorates dextran sulfate sodium-induced colitis in mice. Scand J Gastroenterol 2005; 40:1321-7. [PMID: 16334442 DOI: 10.1080/00365520510023530] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Polaprezinc (N-(3-Aminopropionyl)-L-histidinato zinc), an anti-ulcer drug, has been reported to have an anti-inflammatory action in several inflammatory diseases. The aim of this study was to investigate the effect of polaprezinc on dextran sulfate (DSS)-induced colitis in mice. MATERIAL AND METHODS Mice with colitis induced by DSS were intrarectally treated with polaprezinc (15 mg/kg) or zinc sulfate (7.5 mg/kg) every day after the administration of DSS for 7 days. Disease activity index (DAI) and histological tissue damage were assessed. Levels of myeloperoxidase (MPO) activity, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in the colon were measured. Expression of heat shock protein (HSP) 25 and HSP70 in the colon was analyzed by Western blot analysis. RESULTS DAI and histological scores were remarkably reduced in polaprezinc-treated mice with DSS-induced colitis. Polaprezinc suppressed the increase of MPO activity and the production of TNF-alpha and IFN-gamma in the colon tissues of mice with DSS-induced colitis. Expression of HSP25 and HSP70 was remarkably up-regulated in the colon tissues of polaprezinc-treated mice during DSS treatment. CONCLUSIONS Polaprezinc suppresses DSS-induced colitis in mice, partly through inhibition of production of pro-inflammatory cytokine, suppression of neutrophils accumulation and cytoprotection by overexpression of HSPs. Polaprezinc could be useful in the treatment of inflammatory bowel diseases.
Collapse
Affiliation(s)
- Tatsuya Ohkawara
- Department of Gastroenterology and Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
| | | | | | | | | | | | | |
Collapse
|
27
|
Ohkawara T, Nishihira J, Takeda H, Miyashita K, Kato K, Kato M, Sugiyama T, Asaka M. Geranylgeranylacetone protects mice from dextran sulfate sodium-induced colitis. Scand J Gastroenterol 2005; 40:1049-57. [PMID: 16211708 DOI: 10.1080/00365520510023161] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Geranylgeranylacetone (GGA) has recently been reported to induce heat shock protein (HSP) 70, which has a protective function against inflammation. We investigated the therapeutic effects of oral administration of GGA on dextran sulfate sodium (DSS)-induced colitis in mice. MATERIALS AND METHODS BALB/c mice were given 3% DSS solution orally for 7 days to induce colitis. The disease activity of colitis was assessed clinically every day, and histology in the colon was evaluated at 7 days post-DSS. The levels of myeloperoxidase (MPO) activity, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in the colon tissues were also examined. In addition, expression of HSPs 25, 40, 70 and 90 in the colon tissue was determined by Western blot analysis. Mice were orally administered GGA (50-500 mg/kg) when treatment of DSS started. RESULTS It was found that GGA significantly reduced the clinical severity of colitis and suppressed the levels of MPO activity, TNF-alpha and IFN-gamma induced by DSS in the colon. On the other hand, GGA enhanced the expression of HSP70 in the colon of mice given DSS. CONCLUSIONS Taken together, these results suggest that GGA is a new anti-inflammatory drug that could be useful in the treatment of colitis such as inflammatory bowel disease.
Collapse
Affiliation(s)
- Tatsuya Ohkawara
- Department of Gastroenterology and Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
| | | | | | | | | | | | | | | |
Collapse
|
28
|
Arvans DL, Vavricka SR, Ren H, Musch MW, Kang L, Rocha FG, Lucioni A, Turner JR, Alverdy J, Chang EB. Luminal bacterial flora determines physiological expression of intestinal epithelial cytoprotective heat shock proteins 25 and 72. Am J Physiol Gastrointest Liver Physiol 2005; 288:G696-704. [PMID: 15528251 DOI: 10.1152/ajpgi.00206.2004] [Citation(s) in RCA: 90] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Heat shock proteins (HSP) 25 and 72 are expressed normally by surface colonocytes but not by small intestinal enterocytes. We hypothesized that luminal commensal microflora maintain the observed colonocyte HSP expression. The ability of the small intestine to respond to bacteria and their products and modulate HSPs has not been determined. The effects of luminal bacterial flora in surgically created midjejunal self-filling (SFL) vs. self-emptying (SEL) small-bowel blind loops on epithelial HSP expression were studied. HSP25 and HSP72 expression were assessed by immunoblot and immunohistochemistry. SFL were chronically colonized, whereas SEL contained levels of bacteria normal for the proximal small intestine. SFL creation significantly increased HSP25 and HSP72 expression relative to corresponding sections from SEL. Metronidazole treatment, which primarily affects anaerobic bacteria as well as a diet lacking fermentable fiber, significantly decreased SFL HSP expression. Small bowel incubation with butyrate ex vivo induced a sustained and significant upregulation of HSP25 and altered HSP72 expression, confirming the role of short-chain fatty acids. To determine whether HSPs induction altered responses to an injury, effects of the oxidant, monochloramine, on epithelial resistance and short-circuit current (I(sc)) responses to carbachol and glucose were compared. Increased SFL HSP expression was associated with protection against oxidant-induced decreases in transmural resistance and I(sc) responses to glucose, but not secretory responses to carbachol. In conclusion, luminal microflora and their metabolic byproducts direct expression of HSPs in gut epithelial cells, an effect that contributes to preservation of epithelial cell viability under conditions of stress.
Collapse
Affiliation(s)
- Donna L Arvans
- Martin Boyer Professor of Medicine, The Univ. of Chicago, 5841 S. Maryland Ave. Rm. G705, MC 6084, Chicago, IL, 60637, USA
| | | | | | | | | | | | | | | | | | | |
Collapse
|
29
|
Petrof EO, Ciancio MJ, Chang EB. Role and regulation of intestinal epithelial heat shock proteins in health and disease. ACTA ACUST UNITED AC 2004; 5:45-50. [PMID: 15612656 DOI: 10.1111/j.1443-9573.2004.00154.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Mucosal injury and inflammation are cardinal manifestations of inflammatory bowel diseases (IBD), arising when the effects of cytotoxic factors and conditions overwhelm the cell's capacity for defense (i.e. cytoprotection) or repair. To date, most research in this area has focused primarily on agents and processes involved in producing tissue injury, with less consideration given to inherent mechanisms of cytoprotection and cellular repair. Therapeutic approaches to IBD reflect this bias, being largely directed towards down-regulating the inflammatory process by inhibiting the production of immune and inflammatory mediators. This review will focus on the cell's inherent ability to defend itself against cellular stress and injury through the production of evolutionarily conserved stress proteins called heat shock proteins (HSP). The physiological role of these proteins in maintaining intestinal epithelial cell structure and function will be reviewed, with emphasis on studies that examine the role of HSP in IBD. A clearer understanding of the innate cytoprotective mechanisms inherent in intestinal epithelial cells will foster the development of new insights into basic epithelial cell biology, which ultimately can be used to establish target-specific therapies directed at reducing or alleviating mucosal injury, thereby promoting tissue healing and repair.
Collapse
Affiliation(s)
- Elaine O Petrof
- Section of Infectious Diseases, Department of Medicine, University of Chicago, 60637, USA
| | | | | |
Collapse
|
30
|
Kojima K, Musch MW, Ren H, Boone DL, Hendrickson BA, Ma A, Chang EB. Enteric flora and lymphocyte-derived cytokines determine expression of heat shock proteins in mouse colonic epithelial cells. Gastroenterology 2003; 124:1395-407. [PMID: 12730879 DOI: 10.1016/s0016-5085(03)00215-4] [Citation(s) in RCA: 82] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Inducible heat shock proteins (hsps), particularly hsp25 and hsp72, are expressed by surface colonocytes and may have a role in protecting intestinal epithelial cells against injury. This study is aimed at determining if enteric bacteria and/or immune signals regulate their physiologic expression. METHODS Intestinal hsp25, hsp72, and constitutive hsc73 expression were studied in immunodeficient RAG-1(-/-) mice and in normal mice. Mucosal permeability was measured by mannitol flux and transepithelial resistance. Hsp expression in intestinal YAMC cells was assessed after incubation with recombinant cytokines, activated lamina propria lymphocytes (LPLs), or Bacteroides fragilis. RESULTS Chronic metronidazole treatment decreases colonic mucosal hsp25 and hsp72 expression, an effect associated with increased susceptibility of mucosal barrier function to C. difficile toxin A. Hsp expression also was increased in YAMC cells incubated with B. fragilis, an effect mediated by lipopolysaccharide and other bacteria-derived factors. Colonic hsp72, but not hsp25 or hsc73, expression is decreased in RAG-1(-/-) mice. Recombinant IL-2 and other cytokines enhance YAMC hsp25 and/or hsp72 expression. Activated LPLs induce YAMC hsp expression, an effect blocked by IL-2 neutralizing antibody. CONCLUSIONS Enteric flora and mucosal lymphocytes play a role in maintaining physiologic expression of colonocyte hsp25 and hsp72.
Collapse
Affiliation(s)
- Keishi Kojima
- Department of Medicine, The MArtin Boyer Laboratory, The University of Chicago, Illinois 60637, USA
| | | | | | | | | | | | | |
Collapse
|
31
|
Malago JJ, Koninkx JFJG, van Dijk JE. The heat shock response and cytoprotection of the intestinal epithelium. Cell Stress Chaperones 2003. [PMID: 12380687 DOI: 10.1379/1466-1268(2002)007%3c0191:thsrac%3e2.0.co;2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Following heat stress, the mammalian intestinal epithelial cells respond by producing heat shock proteins that confer protection under stressful conditions, which would otherwise lead to cell damage or death. Some of the noxious processes against which the heat shock response protects cells include heat stress, infection, and inflammation. The mechanisms of heat shock response-induced cytoprotection involve inhibition of proinflammatory cytokine production and induction of cellular proliferation for restitution of the damaged epithelium. This can mean selective interference of pathways, such as nuclear factor kappa B (NF-kappaB) and mitogen-activated protein kinase (MAPK), that mediate cytokine production and growth responses. Insight into elucidating the exact protective mechanisms could have therapeutic significance in treating intestinal inflammations and in aiding maintenance of intestinal integrity. Herein we review findings on heat shock response-induced intestinal epithelial protection involving regulation of NF-kappaB and MAPK cytokine production.
Collapse
Affiliation(s)
- Joshua J Malago
- Department of Veterinary Pathology, Faculty of Veterinary Medicine, Utrecht University, The Netherlands.
| | | | | |
Collapse
|
32
|
Malago JJ, Koninkx JFJG, van Dijk JE. The heat shock response and cytoprotection of the intestinal epithelium. Cell Stress Chaperones 2002; 7:191-9. [PMID: 12380687 PMCID: PMC514817 DOI: 10.1379/1466-1268(2002)007<0191:thsrac>2.0.co;2] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Following heat stress, the mammalian intestinal epithelial cells respond by producing heat shock proteins that confer protection under stressful conditions, which would otherwise lead to cell damage or death. Some of the noxious processes against which the heat shock response protects cells include heat stress, infection, and inflammation. The mechanisms of heat shock response-induced cytoprotection involve inhibition of proinflammatory cytokine production and induction of cellular proliferation for restitution of the damaged epithelium. This can mean selective interference of pathways, such as nuclear factor kappa B (NF-kappaB) and mitogen-activated protein kinase (MAPK), that mediate cytokine production and growth responses. Insight into elucidating the exact protective mechanisms could have therapeutic significance in treating intestinal inflammations and in aiding maintenance of intestinal integrity. Herein we review findings on heat shock response-induced intestinal epithelial protection involving regulation of NF-kappaB and MAPK cytokine production.
Collapse
Affiliation(s)
- Joshua J Malago
- Department of Veterinary Pathology, Faculty of Veterinary Medicine, Utrecht University, The Netherlands.
| | | | | |
Collapse
|
33
|
Fudaba Y, Ohdan H, Tashiro H, Ito H, Fukuda Y, Dohi K, Asahara T. Geranylgeranylacetone, a heat shock protein inducer, prevents primary graft nonfunction in rat liver transplantation. Transplantation 2001; 72:184-9. [PMID: 11477336 DOI: 10.1097/00007890-200107270-00003] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Heat shock proteins (HSPs) are well known as cytoprotective proteins. Geranylgeranylacetone (GGA), a nontoxic anti-ulcer drug, was recently shown to have HSP-inducing capacity. In the present study, the activity of GGA was tested in a rat orthotopic liver transplantation (OLT) model to determine whether the compound has beneficial effects in warm ischemia-reperfusion injury. METHODS Either GGA or a control vehicle was orally administered to donor rats before graft harvest. Harvested livers were subjected to 45-min warm ischemia (37 degrees C) followed by OLT. HSP mRNA expressions and HSP syntheses in the graft livers were evaluated by reverse transcriptase polymerase chain reaction and Western blot analysis, respectively. RESULTS When the donors were treated with a vehicle, all recipients died of primary nonfunction within 2 days after OLT. In contrast, when the donors were treated with GGA (200 mg/kg per day) for 4 weeks, the 7-day survival rate of recipients was dramatically improved (90%). By giving a high dose of GGA (600 mg/kg per day) for 1 week, a similar improvement in recipient survival was seen (83.3%). GGA administration accumulated mRNA for both HSP72 and HSP90 in the livers even before warm ischemia and facilitated the syntheses of HSP72 and HSP90 after warm ischemia. In addition, GGA pretreatment also significantly reduced the serum levels of tumor necrosis factor-alpha (TNF-alpha) after reperfusion. CONCLUSIONS These findings indicate that both the enhanced induction of HSPs and the suppression of a cytotoxic mediator (TNF-alpha) might be involved in the beneficial effects of GGA on ischemia-reperfusion injury. Thus, oral administration of GGA would be a useful tool for preventing primary nonfunction in liver transplantation.
Collapse
Affiliation(s)
- Y Fudaba
- Second Department of Surgery, Hiroshima University, Faculty of Medicine, 1-2-3 Kasumi Minami-ku Hiroshima 734-8551, Japan
| | | | | | | | | | | | | |
Collapse
|
34
|
Tsukimi Y, Okabe S. Recent advances in gastrointestinal pathophysiology: role of heat shock proteins in mucosal defense and ulcer healing. Biol Pharm Bull 2001; 24:1-9. [PMID: 11201234 DOI: 10.1248/bpb.24.1] [Citation(s) in RCA: 80] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The defense mechanism of the gastrointestinal mucosa against aggressive factors, such as hydrochloric acid, bile acid and non-steroidal anti-inflammatory drugs, mainly consists of functional, humoral and neuronal factors. Mucus-alkaline secretion, mucosal microcirculation, and motility act as functional factors, while prostaglandins and nitric oxide act as humoral factors, and capsaicin sensitive sensory neurons act as neuronal factors. All the above factors are known to contribute to mucosal protection. In recent years, heat shock proteins (HSPs), to include HSP70, have been implicated to be an additional factor utilized for the defense mechanisms of the gastrointestinal mucosa at the intracellular level. The expression of HSP70 and HSP47 markedly changes during the development and healing of chronic gastric ulcers in rats. It was revealed that HSC70 (a constitutive form of HSP70) is coprecipitated with cyclooxygenase-1 and the neuronal form of nitric oxide synthase after treatment with a mild irritant (20% ethanol). A positive relationship between enhanced interaction of HSC70 with either cyclooxygenase-1 or nitric oxide synthase and mucosal protection against a strong irritant (100% ethanol) was observed. It was concluded that HSPs might contribute to mucosal defense mechanisms and ulcer healing, most probably through protecting key enzymes related to cytoprotection.
Collapse
Affiliation(s)
- Y Tsukimi
- Department of Applied Pharmacology, Kyoto Pharmaceutical University, Yamashina, Japan
| | | |
Collapse
|
35
|
Goldhill JM, Stojadinovic A, Kiang J, Smallridge R, Shea-Donohue T. Hyperthermia prevents functional, histological and biochemical abnormalities induced during ileitis. Neurogastroenterol Motil 1999; 11:69-76. [PMID: 10087537 DOI: 10.1046/j.1365-2982.1999.00130.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Inflammatory bowel disease is associated with altered intestinal motility and epithelial damage. Hyperthermia induces heat shock protein expression, components of a basic cellular defence mechanism, and consequently prevents ischaemic damage. Here we investigate whether hyperthermia may prevent altered smooth muscle function as well as underlying inflammation in a model of inflammatory bowel disease. Ileal heat shock protein expression was induced in rats by hyperthermic shock (41.5 degrees C; 5 min). Two hours after heating or sham treatment, ileitis was evoked by TNBS. Ileal samples were taken 4 h later to determine the contractile response of circular muscle strips, and to measure heat shock protein expression, LTB4 generation and damage/inflammation. Ileitis was associated with an increase in the contractile response of circular muscle to substance P but not neurokinin A or nerve stimulation. Hyperthermia induced heat shock protein expression and also prevented this functional change as well as TNBS-induced LTB4 production, subsequent infiltration of neutrophils and epithelial damage. Thus, intestinal inflammation is associated with alterations in tachykinergic control of smooth muscle as well as inflammatory changes. Hyperthermia prevents these changes and induces heat shock protein expression. Pharmacological induction of these proteins may offer a novel clinical strategy in treating both of these aspects of disease.
Collapse
Affiliation(s)
- J M Goldhill
- Division of Medicine, USUHS, Bethesda, MD 20814, USA
| | | | | | | | | |
Collapse
|