Pirfenidone and nintedanib modulate properties of fibroblasts and myofibroblasts in idiopathic pulmonary fibrosis

被引：114

作者：

Lehtonen, Siri T. ^{[1
,2
,3
]}

Veijola, Anniina ^{[2
,3
]}

Karvonen, Henna ^{[2
,3
,4
]}

Lappi-Blanco, Elisa ^{[5
,6
]}

Sormunen, Raija ^{[5
,6
,7
]}

Korpela, Saara ^{[1
,2
,3
]}

Zagai, Ulrika ^{[8
]}

Skold, Magnus C. ^{[9
,10
]}

Kaarteenaho, Riitta ^{[2
,3
,11
,12
,13
,14
]}

机构：

[1] Univ Oulu, Dept Anat & Cell Biol, Canc & Translat Med Res Unit, Aapistie 7 A, FIN-90220 Oulu, Finland

[2] Oulu Univ Hosp, Dept Internal Med, Resp Res Unit, Aapistie 5 A, FIN-90220 Oulu, Finland

[3] Oulu Univ Hosp, Med Res Ctr, Aapistie 5 A, FIN-90220 Oulu, Finland

[4] Univ Toronto, Fac Dent, Matrix Dynam Grp, Lab Tissue Repair & Regenerat, 150 Coll St, Toronto, ON M5S 3E2, Canada

[5] Oulu Univ Hosp, Dept Pathol, POB 50, FIN-90029 Oulu, Finland

[6] Univ Oulu, Dept Pathol, Canc & Translat Med Res Unit, Aapistie 5 B, FIN-90220 Oulu, Finland

[7] Univ Oulu, Bioctr Oulu, Aapistie 5 A, FIN-90220 Oulu, Finland

[8] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden

[9] Karolinska Inst, Dept Med Solna, Resp Med Unit, SE-17177 Stockholm, Sweden

[10] Karolinska Inst, Ctr Mol Med, SE-17177 Stockholm, Sweden

[11] Univ Oulu, Resp Res Unit, Res Unit Internal Med, Aapistie 5 A, FIN-90220 Oulu, Finland

[12] Univ Oulu, Med Res Ctr, Aapistie 5 A, FIN-90220 Oulu, Finland

[13] Univ Eastern Finland, Div Pulm, Unit Med & Clin Res, Kuopio, Finland

[14] Kuopio Univ Hosp, Div Resp Med, Ctr Med & Clin Res, SF-70210 Kuopio, Finland

来源：

RESPIRATORY RESEARCH | 2016年 / 17卷

关键词：

Cell culture; Ultrastructure; Usual interstitial pneumonia; UIP; EXPRESSION; MODEL; ACETYLCYSTEINE; INHIBITOR; DIAGNOSIS; TISSUE; HSP47;

D O I：

10.1186/s12931-016-0328-5

中图分类号：

R56 [呼吸系及胸部疾病];

学科分类号：

摘要：

Background: Idiopathic pulmonary fibrosis (IPF) is an incurable lung disease with a poor prognosis. Fibroblasts and myofibroblasts are the key cells in the fibrotic process. Recently two drugs, pirfenidone and nintedanib, were approved for clinical use as they are able to slow down the disease progression. The mechanisms by which these two drugs act in in vitro cell systems are not known. The aim of this study was therefore to examine the effects of pirfenidone and nintedanib on fibroblasts and myofibroblasts structure and function established from patients with or without IPF. Methods: Stromal cells were collected and cultured from control lung (n = 4) or IPF (n = 7). The cells were treated with pirfenidone and/or nintedanib and the effect of treatment was evaluated by measuring cell proliferation, alpha smooth muscle actin (alpha-SMA) and fibronectin expression by Western analysis and/or immunoelectron microscopy, ultrastructural properties by transmission electron microscopy and functional properties by collagen gel contraction and invasion assays. Results: Both pirfenidone and nintedanib reduced in vitro proliferation of fibroblastic cells in a dose dependent manner. The number of cells from control lung was reduced to 47 % (p = 0.04) and of IPF cells to 42 % (p = 0.04) by 1 mM pirfenidone and correspondingly to 67 % (p = 0.04) and 68 % (p = 0.04), by 1 mu M nintedanib. If both drugs were used together, a further reduced proliferation was observed. Both pirfenidone and nintedanib were able to reduce the amount of a-SMA and the myofibroblastic appearance although the level of reduction was cell line dependent. In functional assays, the effect of both drugs was also variable. Conclusions: We conclude that the ultrastructure and function of fibroblasts and myofibroblasts are affected by pirfenidone and nintedanib. Combination of the drugs reduced cell proliferation more than either of them individually. Human lung derived cell culture systems represent a potential platform for screening and testing drugs for fibrotic diseases.

引用

页数：12

共 33 条

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