Chronic sciatic nerve compression induces fibrosis in dorsal root ganglia

Li,Qinwen; Chen,Jianghai; Chen,Yanhua; Cong,Xiaobin; Chen,Zhenbing

doi:10.3892/mmr.2016.4810

Chronic sciatic nerve compression induces fibrosis in dorsal root ganglia

Authors:
- Qinwen Li
- Jianghai Chen
- Yanhua Chen
- Xiaobin Cong
- Zhenbing Chen
View Affiliations

Affiliations: Department of Orthopedics, The First People's Hospital of Yichang, Yichang, Hubei 443000, P.R. China, Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
Published online on: January 27, 2016 https://doi.org/10.3892/mmr.2016.4810
Pages: 2393-2400
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

In the present study, pathological alterations in neurons of the dorsal root ganglia (DRG) were investigated in a rat model of chronic sciatic nerve compression. The rat model of chronic sciatic nerve compression was established by placing a 1 cm Silastic tube around the right sciatic nerve. Histological examination was performed via Masson's trichrome staining. DRG injury was assessed using Fluoro Ruby (FR) or Fluoro Gold (FG). The expression levels of target genes were examined using reverse transcription‑quantitative polymerase chain reaction, western blot and immunohistochemical analyses. At 3 weeks post‑compression, collagen fiber accumulation was observed in the ipsilateral area and, at 8 weeks, excessive collagen formation with muscle atrophy was observed. The collagen volume fraction gradually and significantly increased following sciatic nerve compression. In the model rats, the numbers of FR‑labeled DRG neurons were significantly higher, relative to the sham‑operated group, however, the numbers of FG‑labeled neurons were similar. In the ipsilateral DRG neurons of the model group, the levels of transforming growth factor‑β1 (TGF‑β1) and connective tissue growth factor (CTGF) were elevated and, surrounding the neurons, the levels of collagen type I were increased, compared with those in the contralateral DRG. In the ipsilateral DRG, chronic nerve compression was associated with significantly higher levels of phosphorylated (p)‑extracellular signal‑regulated kinase 1/2, and significantly lower levels of p‑c‑Jun N‑terminal kinase and p‑p38, compared with those in the contralateral DRGs. Chronic sciatic nerve compression likely induced DRG pathology by upregulating the expression levels of TGF‑β1, CTGF and collagen type I, with involvement of the mitogen‑activated protein kinase signaling pathway.

View Figures

View References

1	Pelletier J, Fromy B, Morel G, Roquelaure Y, Saumet JL and Sigaudo-Roussel D: Chronic sciatic nerve injury impairs the local cutaneous neurovascular interaction in rats. Pain. 153:149–157. 2012. View Article : Google Scholar
2	Berger JV, Knaepen L, Janssen SP, Jaken RJ, Marcus MA, Joosten EA and Deumens R: Cellular and molecular insights into neuropathy-induced pain hypersensitivity for mechanism-based treatment approaches. Brain Res Rev. 67:282–310. 2011. View Article : Google Scholar : PubMed/NCBI
3	Pham K and Gupta R: Understanding the mechanisms of entrapment neuropathies. Review article. Neurosurg Focus. 26:E72009. View Article : Google Scholar : PubMed/NCBI
4	Gupta R, Rowshan K, Chao T, Mozaffar T and Steward O: Chronic nerve compression induces local demyelination and remyelination in a rat model of carpal tunnel syndrome. Exp Neurol. 187:500–508. 2004. View Article : Google Scholar : PubMed/NCBI
5	Mackinnon SE: Pathophysiology of nerve compression. Hand Clin. 18:231–241. 2002. View Article : Google Scholar : PubMed/NCBI
6	Mackinnon SE, Dellon AL, Hudson AR and Hunder DA: Chronic human nerve compression - a histological assessment. Neuropathol Appl Neurobiol. 12:547–565. 1986. View Article : Google Scholar : PubMed/NCBI
7	Prinz RA, Nakamura-Pereira M, De-Ary-Pires B, Fernandes D, Fabião-Gomes BD, Martinez AM, de Ary-Pires R and Pires-Neto MA: Axonal and extracellular matrix responses to experimental chronic nerve entrapment. Brain Res. 1044:164–175. 2005. View Article : Google Scholar : PubMed/NCBI
8	Pham Khoa, Nassiri Nima and Gupta Ranjan: c-Jun, krox-20, and integrin β4 expression following chronic nerve compression injury. Neurosci Lett. 465:194–198. 2009. View Article : Google Scholar : PubMed/NCBI
9	Chao T, Pham K, Steward O and Gupta R: Chronic nerve compression injury induces a phenotypic switch of neurons within the dorsal root ganglia. J Comp Neurol. 506:180–193. 2008. View Article : Google Scholar
10	Zhang Y, Wang YH, Zhang XH, Ge HY, Arendt-Nielsen L, Shao JM and Yue SW: Proteomic analysis of differential proteins related to the neuropathic pain and neuroprotection in the dorsal root ganglion following its chronic compression in rats. Exp Brain Res. 189:199–209. 2008. View Article : Google Scholar : PubMed/NCBI
11	Dubovy P, Brazda V, Klusakova I and Hradilova-Svizenska I: Bilateral elevation of interleukin-6 protein and mRNA in both lumbar and cervical dorsal root ganglia following unilateral chronic compression injury of the sciatic nerve. J Neuroinflammation. 10:552013. View Article : Google Scholar : PubMed/NCBI
12	Ponticos M, Papaioannou I, Xu S, et al: The failure to degrade JunB contributes to Collagen type I over-production and dermal fibrosis in Scleroderma. Arthritis Rheumatol. 1:242–253. 2014.
13	Zhu Y, Colak T, Shenoy M, Liu L, Mehta K, Pai R, Zou B, Xie XS and Pasricha PJ: Transforming growth factor beta induces sensory neuronal hyperexcitability and contributes to pancreatic pain and hyperalgesia in rats with chronic pancreatitis. Mol Pain. 8:652012. View Article : Google Scholar
14	Fujii M, Nakanishi H, Toyoda T, Tanaka I, Kondo Y, Osada H and Sekido Y: Convergent signaling in the regulation of connective tissue growth factor in malignant mesothelioma: TGF β signaling and defects in the Hippo signaling cascade. Cell Cycle. 11:3373–3379. 2012. View Article : Google Scholar : PubMed/NCBI
15	Peng B, Chen J, Kuang Z, Li D, Pang X and Zhang X: Expression and role of connective tissue growth factor in painful disc fibrosis and degeneration. Spine (Phila Pa 1976). 34:E178–E182. 2009. View Article : Google Scholar
16	Yang Y, Wu H, Yan JQ, Song ZB and Guo QL: Tumor necrosis factor-α inhibits angiotensin II receptor type 1 expression in dorsal root ganglion neurons via β-catenin signaling. Neuroscience. 248:383–391. 2013. View Article : Google Scholar : PubMed/NCBI
17	Muralidharan A, Wyse BD and Smith MT: Analgesic efficacy and mode of action of a selective small molecule angiotensin II type 2 receptor antagonist in a rat model of prostate cancer-induced bone pain. Pain Med. 15:93–110. 2014. View Article : Google Scholar : PubMed/NCBI
18	Obata K and Noguchi K: MAPK activation in nociceptive neurons and pain hypersensitivity. Life Sci. 74:2643–2653. 2004. View Article : Google Scholar : PubMed/NCBI
19	O'Brien JP, Mackinnon SE, MacLean AR, Hudson AR, Dellon AL and Hunter DA: A model of chronic nerve compression in the rat. Ann Plast Surg. 19:430–435. 1987. View Article : Google Scholar : PubMed/NCBI
20	Zele T, Sketelj J and Bajrovic FF: Efficacy of fluorescent tracers in retrograde labeling of cutaneous afferent neurons in the rat. J Neurosci Methods. 191:208–214. 2010. View Article : Google Scholar : PubMed/NCBI
21	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2^−ΔΔCt method. Methods. 25:402–408. 2001. View Article : Google Scholar
22	Madala SK, Schmidt S, Davidson C, Ikegami M, Wert S and Hardie WD: MEK-ERK pathway modulation ameliorates pulmonary fibrosis associated with epidermal growth factor receptor activation. Am J Respir Cell Mol Biol. 46:380–388. 2012. View Article : Google Scholar :
23	Gao X, Wu G, Gu X, Fu L and Mei C: Kruppel-like factor 15 modulates renal interstitial fibrosis by ERK/MAPK and JNK/MAPK pathways regulation. Kidney Blood Press Res. 37:631–640. 2013. View Article : Google Scholar : PubMed/NCBI
24	Ma FY, Tesch GH and Nikolic-Paterson DJ: ASK1/p38 signaling in renal tubular epithelial cells promotes renal fibrosis in the mouse obstructed kidney. Am J Physiol Renal Physiol. 307:F1263–F1273. 2014. View Article : Google Scholar : PubMed/NCBI
25	Kawarai Y, Suzuki M, Yoshino K, Inoue G, Orita S, Yamauchi K, Aoki Y, Ishikawa T, Miyagi M, Kamoda H, et al: Transient receptor potential vanilloid 1-immunoreactive innervation increases in fractured rat femur. Yonsei Med J. 55:185–190. 2014. View Article : Google Scholar :
26	Lasko L, Huang X, Voorbach MJ, Lewis LG, Stavropoulos J, Carriker J, Seifert TR, Baker SJ and Upadhyay J: Multimodal assessment of nervous and immune system responses following sciatic nerve injury. Pain. 154:2782–2793. 2013. View Article : Google Scholar : PubMed/NCBI
27	Jones CA, Liang L, Lin D, Jiao Y and Sun B: The spatial-temporal characteristics of type I collagen-based extracellular matrix. Soft Matter. 10:8855–8863. 2014. View Article : Google Scholar : PubMed/NCBI
28	Cheret J, Lebonvallet N, Buhe V, Carre JL, Misery L and Le Gall-Ianotto C: Influence of sensory neuropeptides on human cutaneous wound healing process. J Dermatol Sci. 74:193–203. 2014. View Article : Google Scholar : PubMed/NCBI
29	Koopmans G, Hasse B and Sinis N: Chapter 19: The role of collagen in peripheral nerve repair. Int Rev Neurobiol. 87:363–379. 2009. View Article : Google Scholar : PubMed/NCBI
30	Ihn H: Pathogenesis of fibrosis: Role of TGF-beta and CTGF. Curr Opin Rheumatol. 14:681–685. 2002. View Article : Google Scholar : PubMed/NCBI
31	Leask A, Holmes A, Black CM and Abraham DJ: Connective tissue growth factor gene regulation. Requirements for its induction by transforming growth factor-beta 2 in fibroblasts. J Biol Chem. 278:13008–13015. 2003. View Article : Google Scholar : PubMed/NCBI
32	Igarashi A, Okochi H, Bradham DM and Grotendorst GR: Regulation of connective tissue growth factor gene expression in human skin fibroblasts and during wound repair. Mol Biol Cell. 4:637–645. 1993. View Article : Google Scholar : PubMed/NCBI
33	Boerma M, Wang J, Sridharan V, Herbert JM and Hauer-Jensen M: Pharmacological induction of transforming growth factor-beta1 in rat models enhances radiation injury in the intestine and the heart. PLoS One. 8:e704792013. View Article : Google Scholar : PubMed/NCBI
34	Sonnylal S, Xu S, Jones H, Tam A, Sreeram VR, Ponticos M, Norman J, Agrawal P, Abraham D and De Crombrugghe B: Connective tissue growth factor causes EMT-like cell fate changes in vivo and in vitro. J Cell Sci. 126:2164–2175. 2013. View Article : Google Scholar : PubMed/NCBI
35	George J and Tsutsumi M: siRNA-mediated knockdown of connective tissue growth factor prevents N-nitrosodimethylami ne-induced hepatic fibrosis in rats. Gene Ther. 14:790–803. 2007. View Article : Google Scholar : PubMed/NCBI
36	Gressner OA and Gressner AM: Connective tissue growth factor: A fibrogenic master switch in fibrotic liver diseases. Liver Int. 28:1065–1079. 2008. View Article : Google Scholar : PubMed/NCBI
37	Stark B, Carlstedt T and Risling M: Distribution of TGF-beta, the TGF-beta type I receptor and the R-II receptor in peripheral nerves and mechanoreceptors; observations on changes after traumatic injury. Brain Res. 913:47–56. 2001. View Article : Google Scholar : PubMed/NCBI
38	Abreu JG, Ketpura NI, Reversade B and De Robertis EM: Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-beta. Nat Cell Biol. 4:599–604. 2002.PubMed/NCBI
39	Liu Y, Liu Z, Liu X, Luo B, Xiong J, Gan W, Jiang M and Zhang Z, Schluesener HJ and Zhang Z: Accumulation of connective tissue growth factor+ cells during the early phase of rat traumatic brain injury. Diagn Pathol. 9:1412014. View Article : Google Scholar : PubMed/NCBI
40	Petito RB, Amadeu TP, Pascarelli BM, Jardim MR, Vital RT, Antunes SL and Sarno EN: Transforming growth factor-β1 may be a key mediator of the fibrogenic properties of neural cells in leprosy. J Neuropathol Exp Neurol. 72:351–366. 2013. View Article : Google Scholar : PubMed/NCBI
41	Peti W and Page R: Molecular basis of MAP kinase regulation. Protein Sci. 22:1698–1710. 2013. View Article : Google Scholar : PubMed/NCBI
42	Okada Y, Shirai K, Reinach PS, Kitano-Izutani A, Miyajima M, Flanders KC, Jester JV, Tominaga M and Saika S: TRPA1 is required for TGF-β signaling and its loss blocks inflammatory fibrosis in mouse corneal stroma. Lab Invest. 94:1030–1041. 2014. View Article : Google Scholar : PubMed/NCBI
43	Zhang YP, Wang WL, Liu J, Li WB, Bai LL, Yuan YD and Song SX: Plasminogen activator inhibitor-1 promotes the proliferation and inhibits the apoptosis of pulmonary fibroblasts by Ca (2+) signaling. Thromb Res. 131:64–71. 2013. View Article : Google Scholar
44	Zhang JL, Yang JP, Zhang JR, Li RQ, Wang J, Jan JJ and Zhuang Q: Gabapentin reduces allodynia and hyperalgesia in painful diabetic neuropathy rats by decreasing expression level of Nav1.7 and p-ERK1/2 in DRG neurons. Brain Res. 1493:13–18. 2013. View Article : Google Scholar
45	Zang Y, Xin WJ, Pang RP, Li YY and Liu XG: Upregulation of Nav1.3 Channel Induced by rrTNF in Cultured Adult Rat DRG Neurons via p38 MAPK and JNK Pathways. Chin J Physiol. 54:241–246. 2011. View Article : Google Scholar : PubMed/NCBI