Periostin, a matricellular protein, plays a role in the induction of chemokines in pulmonary fibrosis - PubMed (original) (raw)

doi: 10.1165/rcmb.2011-0115OC. Epub 2012 Jan 12.

Hiroshi Shiraishi, Shoichiro Ohta, Kazuhiko Arima, Kazuto Taniguchi, Shoichi Suzuki, Masaki Okamoto, Shawn K Ahlfeld, Koichi Ohshima, Seiya Kato, Shuji Toda, Hironori Sagara, Hisamichi Aizawa, Tomoaki Hoshino, Simon J Conway, Shinichiro Hayashi, Kenji Izuhara

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Periostin, a matricellular protein, plays a role in the induction of chemokines in pulmonary fibrosis

Masaru Uchida et al. Am J Respir Cell Mol Biol. 2012 May.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal form of interstitial lung disease (ILD). The precise molecular mechanisms of IPF remain poorly understood. However, analyses of mice receiving bleomycin (BLM) as a model of IPF established the importance of preceding inflammation for the formation of fibrosis. Periostin is a recently characterized matricellular protein involved in modulating cell functions. We recently found that periostin is highly expressed in the lung tissue of patients with IPF, suggesting that it may play a role in the process of pulmonary fibrosis. To explore this possibility, we administered BLM to periostin-deficient mice, and they subsequently showed a reduction of pulmonary fibrosis. We next determined whether this result was caused by a decrease in the preceding recruitment of neutrophils and macrophages in the lungs because of the lower production of chemokines and proinflammatory cytokines. We performed an in vitro analysis of chemokine production in lung fibroblasts, which indicated that periostin-deficient fibroblasts produced few or no chemokines in response to TNF-α compared with control samples, at least partly explaining the lack of inflammatory response and, therefore, fibrosis after BLM administration to periostin-deficient mice. In addition, we confirmed that periostin is highly expressed in the lung tissue of chemotherapeutic-agent-induced ILD as well as of patients with IPF. Taking these results together, we conclude that periostin plays a unique role as an inducer of chemokines to recruit neutrophils and macrophages important in the process of pulmonary fibrosis in BLM-administered model mice. Our results suggest a therapeutic potential for periostin in IPF and drug-induced ILD.

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Figures

Figure 1.

Figure 1.

Expression of periostin in lung tissue of bleomycin (BLM)–challenged mice. (A) Kinetic analysis of periostin expression in lung tissue of BLM-administered BALB/c mice. Staining with hematoxylin-and-eosin (H&E) and Masson trichrome, and immunostaining with anti-periostin antibody (Ab), are shown. (B) Quantification of periostin-positive areas at 4 weeks. (C) Localization of periostin and α–smooth muscle actin (α-SMA) in lungs of pulmonary fibrosis model mice. Lung sections of BALB/c mice at 4 weeks in A were stained with anti-periostin Ab and anti–α-SMA Ab. An immunofluorescence image (green, periostin;red, α-SMA) is shown. AU, arbitrary units; V, vessel; wk, weeks.

Figure 2.

Figure 2.

Periostin is important for the progression of pulmonary fibrosis in BLM-challenged mice. BLM was administered intratracheally into wild-type periostin-deficient (_Postn_−/−) or heterozygous (Postn+/−) mice (BALB/c background) on Day 0, or BLM was administered intraperitoneally into wild-type or_Postn_−/− mice (C57BL/6 background) three times on Days 0, 7, and 14. Lung tissue was prepared on Day 28. The survival rates (BALB/c; A), lung histology (BALB/c and C57BL/6;B), Ashcroft scores of pulmonary fibrosis (BALB/c and C57BL/6; C), and amounts of hydroxyproline in a lung (BALB/c;D) are shown. Lung histology was analyzed by hematoxylin-and-eosin and Masson trichrome staining, and immunostaining involved anti-periostin Ab.

Figure 3.

Figure 3.

Periostin is important for the induction of inflammation in BLM-challenged mice. BLM or saline was administered intratracheally into wild-type or periostin-deficient mice (BALB/c background) on Day 0. Bronchoalveolar lavage fluid (BALF) and the lung tissue were prepared on Day 7. The numbers of total cells, neutrophils, macrophages, lymphocytes, and eosinophils in BALF from saline-administered (n = 8) or BLM-administered wild-type mice (n = 16) or BLM-administered periostin-deficient mice (n = 8) are shown.

Figure 4.

Figure 4.

Periostin is important for the induction of chemokines and proinflammatory cytokines in BLM-challenged mice. RNA (A) or proteins (B) were extracted from lung tissue 7 days after BLM treatment, and prepared as shown in Figure 3. RNA was applied to real-time PCR for Ccl2/MCP1, Ccl4/MIP-1B, Ccl7/MCP3, Cxcl1/KC, Cxcl2/MIP-2a, TNF-α, and IL-1β. The relative mRNA concentrations of each chemokine or cytokine in saline-administered (n = 8) or BLM-administered (n = 16) wild-type mice or BLM-administered, periostin-deficient mice (n = 8) are shown. Protein concentrations of TNF-α and IL-1β from saline-administered (n = 8) or BLM-administered (n = 15) wild-type mice or BLM-administered periostin-deficient mice (n = 6) are shown.

Figure 5.

Figure 5.

Periostin is important for the induction of chemokines and proinflammatory cytokines in fibroblasts. Wild-type (WT) or periostin-deficient (KO) fibroblasts were stimulated without (UT) or with (TNF) 20 ng/ml of TNF-α for 72 hours. RNA extracted from fibroblasts was applied to real-time PCR for Ccl2/MCP1, Ccl4/MIP-1B, Ccl7/MCP3, Cxcl1/KC, Cxcl2/MIP-2a, and IL-1β.

Figure 6.

Figure 6.

Expression of periostin in lung tissue of patients with BLM-induced or gefitinib-induced ILD. (A) Expression of periostin in control subjects, patients with UIP, BLM-administered patients, and gefitinib-administered patients. Hematoxylin-and-eosin (H&E) staining and immunostaining with anti-periostin Ab in lung tissue obtained from a representative control subject (64-year-old male), a patient with UIP (64-year-old male), BLM-administered patients (56-year-old male and 67-year-old female), and gefitinib-administered patients (66-year-old female and 73-year-old male) are shown. Arrow indicates expressed periostin. (B) Localization of periostin and α-SMA in the lungs of a gefitinib-administered patient (69-year-old female). Lung sections were stained with anti-periostin Ab and anti–α-SMA Ab. An immunofluorescence image (green, periostin; red, α-SMA) is shown. V, vessel.

References

    1. Strieter RM. Pathogenesis and natural history of usual interstitial pneumonia: the whole story or the last chapter of a long novel? Chest 2005;128:526S–532S. -PubMed
    1. Gharaee-Kermani M, Gyetko MR, Hu B, Phan SH. New insights into the pathogenesis and treatment of idiopathic pulmonary fibrosis: a potential role for stem cells in the lung parenchyma and implications for therapy. Pharm Res 2007;24:819–841. -PubMed
    1. Moore BB, Hogaboam CM. Murine models of pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2008;294:L152–L160. -PubMed
    1. Baran CP, Opalek JM, McMaken S, Newland CA, O'Brien JM, Hunter MG, Bringardner BD, Monick MM, Brigstock DR, Stromberg PC, et al. Important roles for macrophage colony–stimulating factor, CC chemokine ligand 2, and mononuclear phagocytes in the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med 2007;176:78–89. -PMC -PubMed
    1. Russo RC, Guabiraba R, Garcia CC, Barcelos LS, Roffe E, Souza AL, Amaral FA, Cisalpino D, Cassali GD, Doni A, et al. Role of the chemokine receptor CXCR2 in bleomycin-induced pulmonary inflammation and fibrosis. Am J Respir Cell Mol Biol 2009;40:410–421. -PubMed

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