Upregulation of receptor tyrosine kinase-like orphan receptor 2 in idiopathic pulmonary fibrosis
0
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Background/Aims: Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a major regulator of Wnt signaling, which is involved in fibroblast dysfunction. Because its role has not been evaluated in idiopathic pulmonary fibrosis (IPF), we examined the clinical implications of ROR2 expression. Methods: ROR2 mRNA expression was measured using reverse transcription polymerase chain reaction in lung tissue-derived fibroblasts from IPF patients (n = 14) and from controls (n = 10). ROR2 protein was measured using enzyme-linked immunosorbent assay in primary fibroblasts from IPF patients (n = 14) and controls (n = 10), and in bronchoalveolar lavage (BAL) fluids obtained from normal controls (NC; n = 30). IPF patients (n = 84), and other patients with interstitial lung diseases, including nonspecific interstitial pneumonia (NSIP; n = 10), hypersensitivity pneumonitis (HP; n = 10), and sarcoidosis (n = 10). Results: ROR2 mRNA and protein levels were significantly higher in IPF fibroblasts than in controls (p = 0.003, p = 0.0017, respectively). ROR2 protein levels in BAL fluids from patients with IPF were significantly higher than in those from NC (p < 0.001), and from patients with NSIP (p = 0.006), HP (p = 0.004), or sarcoidosis (p = 0.004). Receiver operating characteristic curves showed a clear difference between IPF and NC in ROR2 protein level (area under the curve, 0.890; confidence interval, 0.829 to 0.950; p < 0.001). ROR2 protein levels were significantly higher in GAP stage III than in GAP stages I and II (p = 0.016). Conclusions: ROR2 may be related to the development of IPF, and its protein level may be a useful and severity-dependent candidate marker for IPF.
Abstract
Background/Aims: Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a major regulator of Wnt signaling, which is involved in fibroblast dysfunction. Because its role has not been evaluated in idiopathic pulmonary fibrosis (IPF), we examined the clinical implications of ROR2 expression. Methods: ROR2 mRNA expression was measured using reverse transcription polymerase chain reaction in lung tissue-derived fibroblasts from IPF patients (n = 14) and from controls (n = 10). ROR2 protein was measured using enzyme-linked immunosorbent assay in primary fibroblasts from IPF patients (n = 14) and controls (n = 10), and in bronchoalveolar lavage (BAL) fluids obtained from normal controls (NC; n = 30). IPF patients (n = 84), and other patients with interstitial lung diseases, including nonspecific interstitial pneumonia (NSIP; n = 10), hypersensitivity pneumonitis (HP; n = 10), and sarcoidosis (n = 10). Results: ROR2 mRNA and protein levels were significantly higher in IPF fibroblasts than in controls (p = 0.003, p = 0.0017, respectively). ROR2 protein levels in BAL fluids from patients with IPF were significantly higher than in those from NC (p < 0.001), and from patients with NSIP (p = 0.006), HP (p = 0.004), or sarcoidosis (p = 0.004). Receiver operating characteristic curves showed a clear difference between IPF and NC in ROR2 protein level (area under the curve, 0.890; confidence interval, 0.829 to 0.950; p < 0.001). ROR2 protein levels were significantly higher in GAP stage III than in GAP stages I and II (p = 0.016). Conclusions: ROR2 may be related to the development of IPF, and its protein level may be a useful and severity-dependent candidate marker for IPF.
참고문헌 (43)
- Wahidi M, "Idiopathic Pulmonary Fibrosis", pp.31~54 (2003), CRC Press
- Schwartz DA, "Idiopathic pulmonary fibrosis is a complex genetic disorder", Trans Am Clin Climatol Assoc, 127, pp.34~45 (2016)
- Boon K, "Molecular phenotypes distinguish patients with relatively stable from progressive idiopathic pulmonary fibrosis (IPF)", PLoS One, 4, pp.e5134~ (2009)
- Konishi K, "Gene expression profiles of acute exacerbations of idiopathic pulmonary fibrosis", Am J Respir Crit Care Med, 180, pp.167~175 (2009)
- Selman M, "Gene expression profiles distinguish idiopathic pulmonary fibrosis from hypersensitivity pneumonitis", Am J Respir Crit Care Med, 173, pp.188~198 (2006)
- Zuo F, "Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans", Proc Natl Acad Sci U S A, 99, pp.6292~6297 (2002)
- Kim DS, "Classification and natural history of the idiopathic interstitial pneumonias", Proc Am Thorac Soc, 3, pp.285~292 (2006)
- Wynn TA, "Integrating mechanisms of pulmonary fibrosis", J Exp Med, 208, pp.1339~1350 (2011)
- Lee JU, "Gene profile of fibroblasts identify relation of CCL8 with idiopathic pulmonary fibrosis", Respir Res, 18, pp.3~ (2017)
- Logan CY, "The Wnt signaling pathway in development and disease", Annu Rev Cell Dev Biol, 20, pp.781~810 (2004)
- Vuga LJ, "WNT5A is a regulator of fibroblast proliferation and resistance to apoptosis", Am J Respir Cell Mol Biol, 41, pp.583~589 (2009)
- Oishi I, "The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a", JNK signalling pathway, 2003, pp.8, 645~654
- Takahashi D, "Expression of Ror2associated with fibrosis of the submandibular gland", Cell Struct Funct, 42, pp.159~167 (2017)
- American Thoracic Society(ATS), "Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement", Am J Respir Crit Care Med, 161(2 Pt 1), pp.646~664 (2000)
- Selman M, "Hypersensitivity pneumonitis : insights in diagnosis and pathobiology", Am J Respir Crit Care Med, 186, pp.314~324 (2012)
- Parrish S, "Diagnosis of sarcoidosis", Dis Mon, 55, pp.693~703 (2009)
- Baughman RP, "A concise review of pulmonary sarcoidosis", Am J Respir Crit Care Med, 183, pp.573~581 (2011)
- Travis WD, "An official American Thoracic Society", European Respiratory Society statement : update of the international multidisciplinary classification of the idiopathic interstitial pneumonias, 2013, pp.188, 733~748
- American Thoracic Society, "American Thoracic Society", European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001, 2002, pp.165, 277~304
- Raghu G, "An official ATS", ERS, ALAT statement : idiopathic pulmonary fibrosis : evidence-based guidelines for diagnosis and management, pp.Am J Respir Crit Care Med, 2011[DOI]
- Raghu G, "Diagnosis of idiopathic pulmonary fibrosis. An official ATS", ERS, ALAT clinical practice guideline, pp.Am J Respir Crit Care Med, 2018[DOI]
- Katzenstein AL, "Nonspecific interstitial pneumonia", fibrosis. Histologic features and clinical significance, 1994, pp.18, 136~147
- Lee JU, "Global DNA methylation pattern of fibroblasts in idiopathic pulmonary fibrosis", DNA Cell Biol, 38, pp.905~914 (2019)
- Kim TH, "Role of lung apolipoprotein A-I in idiopathic pulmonary fibrosis : antiinflammatory and antifibrotic effect on experimental lung injury and Fibrosis", Am J Respir Crit Care Med, 182, pp.633~642 (2010)
- 박성우, "Interleukin-13 and Its Receptors in Idiopathic Interstitial Pneumonia: Clinical Implications for Lung Function", Journal of Korean Medical Science, 24(4), pp.614~620 (2009), 대한의학회
- Ley B, "A multidimensional index and staging system for idiopathic pulmonary fibrosis", Ann Intern Med, 156, pp.684~691 (2012)
- DeLong ER, "Comparing the areas under two or more correlated receiver operating characteristic curves : a nonparametric approach", Biometrics, 44, pp.837~845 (1988)
- Rosas IO, "MMP1 and MMP7as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis", PLoS Med, 5, pp.e93~ (2008)
- Cai M, "CCL18 in serum, BAL fluid and alveolar macrophage culture supernatant in interstitial lung diseases", Respir Med, 107, pp.1444~1452 (2013)
- Korthagen NM, "Serum and BALF YKL-40 levels are predictors of survival in idiopathic pulmonary fibrosis", Respir Med, 105, pp.106~113 (2011)
- Wang K, "Impact of serum SP-A and SP-D levels on comparison and prognosis of idiopathic pulmonary fibrosis: a systematic review and meta-analysis", Medicine (Baltimore), 96, pp.e7083~ (2017)
- Hamai K, "Comparative study of circulating MMP-7, CCL18, KL-6, SP-A, and SP-D as disease markers of idiopathic pulmonary fibrosis", Dis Markers, 2016, pp.4759040~ (2016)
- Yoda A, "Expression and function of the Ror-family receptor tyrosine kinases during development : lessons from genetic analyses of nematodes, mice, and humans", J Recept Signal Transduct Res, 23, pp.1~15 (2003)
- Schwabe GC, "Ror2 knock out mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome", Dev Dyn, 229, pp.400~410 (2004)
- Masiakowski P, "A novel family of cell surface receptors with tyrosine kinase-like domain", J Biol Chem, 267, pp.26181~26190 (1992)
- Li C, "Ror2 modulates the canonical Wnt signaling in lung epithelial cells through cooperation with Fzd2", BMC Mol Biol, 9, pp.11~ (2008)
- Yamaguchi TP, "A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo", Development, 126, pp.1211~1223 (1999)
- Liang H, "Wnt5a inhibits B cell proliferation and functions as a tumor suppressor in hematopoietic tissue", Cancer Cell, 4, pp.349~360 (2003)
- Sato A, "Wnt5a regulates distinct signalling pathways by binding to Frizzled2", EMBO J, 29, pp.41~54 (2010)
- Pereira C, "Wnt5A", CaMKII signaling contributes to the inflammatory response of macrophages and is a target for the antiinflammatory action of activated protein C and interleukin-10, 2008, pp.28, 504~510
- Mikels A, "Ror2 receptor requires tyrosine kinase activity to mediate Wnt5A signaling", J Biol Chem, 284, pp.30167~30176 (2009)
- Blumenthal A, "The Wingless homolog WNT5A and its receptor Frizzled-5 regulate inflammatory responses of human mononuclear cells induced by microbial stimulation", Blood, 108, pp.965~973 (2006)
- Naskar D, "Wnt5a-Rac1-NF-κB homeostatic circuitry sustains innate immune functions in macrophages", J Immunol, 192, pp.4386~4397 (2014)