Therapeutic effect of ulinastatin on pulmonary fibrosis via downregulation of TGF‑β1, TNF‑α and NF‑κB

Li,Dejun; Ji,Hongsheng; Zhao,Bao; Xu,Chunyang; Xia,Wenjun; Han,Lihui; Yu,Dongqing; Ju,Yuanrong; Jin,Changjun

doi:10.3892/mmr.2017.8056

Therapeutic effect of ulinastatin on pulmonary fibrosis via downregulation of TGF‑β1, TNF‑α and NF‑κB

Authors:
- Dejun Li
- Hongsheng Ji
- Bao Zhao
- Chunyang Xu
- Wenjun Xia
- Lihui Han
- Dongqing Yu
- Yuanrong Ju
- Changjun Jin
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Affiliations: Surgical Intensive Care Unit, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
Published online on: November 14, 2017 https://doi.org/10.3892/mmr.2017.8056
Pages: 1717-1723
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Pulmonary fibrosis is a chronic, progressive, lethal lung disease characterized by alveolar cell necrosis and dysplasia of interstitial fibrotic tissue, resulting in loss of lung function and eventual respiratory failure. Previously, glucocorticoid drugs were used to treat this lung disorder. However, positive responses were recorded in less than half of treated patients and the cytotoxicity caused by high dosage treatment is still a concern. The present study investigated whether ulinastatin, a typical urinary trypsin inhibitor that mitigates numerous inflammatory responses, could be a treatment option for lung fibrosis. The results demonstrated that ulinastatin had the ability to ameliorate interstitial fibrosis and alveolar exudates and to protect against lung diseases induced by smoke, irradiation or silica particles. The mechanism of ulinastatin resulted in the downregulation of inflammatory cascades: Transforming growth factor‑β1, tumor necrosis factor‑α and nuclear factor‑κB, as demonstrated by western blotting and ELISA. Ulinastatin treatment with a high dose (100,000 U/kg body weight/day) resulted in an attenuated inflammatory response, and inhibited fibrosis formation in lungs, suggesting that ulinastatin may become a part of a clinical therapeutic strategy.

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1	Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier JF, Flaherty KR, Lasky JA, et al: An official ATS/ERS/JRS/ALAT statement: Idiopathic pulmonary fibrosis: Evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 183:788–824. 2011. View Article : Google Scholar :
2	Raghu G, Weycker D, Edelsberg J, Bradford WZ and Oster G: Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 174:810–816. 2006. View Article : Google Scholar
3	Gribbin J, Hubbard RB, Le Jeune I, Smith CJ, West J and Tata LJ: Incidence and mortality of idiopathic pulmonary fi brosis and sarcoidosis in the UK. Thorax. 61:980–985. 2006. View Article : Google Scholar :
4	American Thoracic Society; European Respiratory Society: American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumon Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS executive committee, June 2001. Am J Respir Crit Care Med. 165:277–304. 2002.
5	Henderson WR Jr, Chi EY, Ye X, Nguyen C, Tien YT, Zhou B, Borok Z, Knight DA and Kahn M: Inhibition of Wnt/beta-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis. Proc Natl Acad Sci USA. 107:14309–14314. 2010. View Article : Google Scholar :
6	Kanai T, Ishiwata T, Kobayashi T, Sato H, Takizawa M, Kawamura Y, Tsujimoto H, Nakatani K, Ishibashi N, Nishiyama M, et al: Ulinastatin, a urinary trypsin inhibitor, for the initial treatment of patients with Kawasaki disease: A retrospective study. Circulation. 124:2822–2828. 2011. View Article : Google Scholar
7	Sato H, Kajikawa S, Kuroda S, Horisawa Y, Nakamura N, Kaga N, Kakinuma C, Kato K, Morishita H, Niwa H and Miyazaki J: Impaired fertility in female mice lacking urinary trypsin inhibitor. Biochem Biophys Res Commun. 281:1154–1160. 2001. View Article : Google Scholar
8	Umeadi C, Kandeel F and Al-Abdullah IH: Ulinastatin is a novel protease inhibitor and neutral protease activator. Transplant Proc. 40:387–389. 2008. View Article : Google Scholar
9	Pugia MJ and Lott JA: Pathophysiology and diagnostic value of urinary trypsin inhibitors. Clin Chem Lab Med. 43:1–16. 2005. View Article : Google Scholar
10	Wang G, Wen J, Wilbur RR, Wen P, Zhou SF and Xiao X: The effect of somatostatin, ulinastatin and Salvia miltiorrhiza on severe acute pancreatitis treatment. Am J Med Sci. 346:371–376. 2013. View Article : Google Scholar
11	Wei W, Ma B, Li HY, Jia Y, Lv K, Wang G, Zhang J, Zhu S, Tang H, Sheng Z and Xia Z: Biphasic effects of selective inhibition of transforming growth factor beta1 activin receptor-like kinase on LPS-induced lung injury. Shock. 33:218–224. 2010. View Article : Google Scholar
12	Wang J: Care and Use of Laboratory Animals. 8th edition. Shanghai Science and Technology Press; 2012, View Article : Google Scholar
13	O'connor WN and Valle S: A combination Verhoeffs elastic and Masson's trichrome stain for routine histology. Stain Technol. 57:207–210. 1982. View Article : Google Scholar
14	Szapiel SV, Elson NA, Fulmer JD, Hunninghake GW and Crystal RG: Bleomycin-induced interstitial pulmonary disease in the nude, athymic rat. Am Rev Respir Dis. 120:893–899. 1979.
15	Hakenjos L, Bamberg M and Rodemann HP: TGF-beta1-mediated alterations of rat lung fibroblast differentiation resulting in the radiation-induced fibrotic phenotype. Int J Radiat Biol. 76:503–509. 2000. View Article : Google Scholar
16	Moore BB and Hogaboam CM: Murine models of pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 294:L152–L160. 2008. View Article : Google Scholar
17	King TE Jr, Pardo A and Selman M: Idiopathic pulmonary fibrosis. Lancet. 378:1949–1961. 2011. View Article : Google Scholar
18	American Thoracic Society. Idiopathic pulmonary fibrosis: Idiopathic pulmonary fibrosis: Diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Resp Crit Care Med. 161:646–664. 2000. View Article : Google Scholar
19	Tobin RW, Pope CE II, Pellegrini CA, Emond MJ, Sillery J and Raghu G: Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis. Am J Resp Crit Care Med. 158:1804–1808. 1998. View Article : Google Scholar
20	Wang X, Xue Q, Yan F, Li L, Liu J, Li S and Hu S: Ulinastatin as a neuroprotective and anti-inflammatory agent in infant piglets model undergoing surgery on hypothermic low-flow cardiopulmonary bypass. Pediatr Anesth. 23:209–216. 2013. View Article : Google Scholar
21	Shin IW, Jang IS, Lee SM, Park KE, Ok SH, Sohn JT, Lee HK and Chung YK: Myocardial protective effect by ulinastatin via an anti-inflammatory response after regional ischemia/reperfusion injury in an in vivo rat heart model. Korean J Anesthesiol. 61:499–505. 2011. View Article : Google Scholar :
22	Park KH, Lee KH, Kim H and Hwang SO: The anti-inflammatory effects of ulinastatin in trauma patients with hemorrhagic shock. J Korean Med Sci. 25:128–134. 2010. View Article : Google Scholar
23	Gao CJ, Huan JN, Li W and Tang JJ: Protective effects of ulinastatin on pancreatic and renal damage in rats following early scald injury. Burns. 35:547–552. 2009. View Article : Google Scholar
24	Larsen C, Ostergaard J, Larsen SW, Jensen H, Jacobsen S, Lindegaard C and Andersen PH: Intra-articular depot formulation principles: role in the management of postoperative pain and arthritic disorders. J Pharm Sci. 97:4622–4654. 2008. View Article : Google Scholar
25	Ning XH, Ge XF, Cui Y and An HX: Ulinastatin inhibits unilateral ureteral obstruction-induced renal interstitial fibrosis in rats via transforming growth factor β (TGF-β)/Smad signalling pathways. Int Immunopharmacol. 15:406–413. 2013. View Article : Google Scholar
26	Inoue K, Takano H, Yanagisawa R, Sakurai M, Shimada A, Yoshino S, Sato H and Yoshikawa T: Protective role of urinary trypsin inhibitor in acute lung injury induced by lipopolysaccharide. Exp Biol Med (Maywood). 230:281–287. 2005. View Article : Google Scholar
27	Tanaka R, Fujita M, Tsuruta R, Fujimoto K, Aki HS, Kumagai K, Aoki T, Kobayashi A, Izumi T, Kasaoka S, et al: Urinary trypsin inhibitor suppresses excessive generation of superoxide anion radical, systemic inflammation, oxidative stress, and endothelial injury in endotoxemic rats. Inflamm Res. 59:597–606. 2010. View Article : Google Scholar
28	Molor-Erdene P, Okajima K, Isobe H, Uchiba M, Harada N and Okabe H: Urinary trypsin inhibitor reduces LPS-induced hypotension by suppressing tumor necrosis factor-alpha production through inhibition of Egr-1 expression. Am J Physiol Heart Circ Physiol. 288:H1265–H1271. 2005. View Article : Google Scholar
29	Park KJ, Oh YT, Kil WJ, Park W, Kang SH and Chun M: Bronchoalveolar lavage findings of radiation induced lung damage in rats. J Radiat Res. 50:177–182. 2009. View Article : Google Scholar
30	Anscher MS, Kong FM, Andrews K, Clough R, Marks LB, Bentel G and Jirtle RL: Plasma transforming growth factor beta1 as a predictor of radiation pneumonitis. Int J Radiat Oncol Biol Phys. 41:1029–1035. 1998. View Article : Google Scholar
31	Chen G and Goeddel DV: TNF-R1 signaling: A beautiful pathway. Science. 296:1634–1635. 2002. View Article : Google Scholar
32	Ghosh S, May MJ and Kopp EB: NF-kappa B and Rel proteins: Evolutionarily conserved mediators of immune responses. Ann Rev Immunol. 16:225–260. 1998. View Article : Google Scholar
33	Cox RA, Burke AS, Jacob S, Oliveras G, Murakami K, Shimoda K, Enkhbaatar P, Traber LD, Herndon DN, Traber DL and Hawkins HK: Activated nuclear factor kappa B and airway inflammation after smoke inhalation and burn injury in sheep. J Burn Care Res. 30:489–498. 2009. View Article : Google Scholar