All Title Author
Keywords Abstract

Publish in OALib Journal
ISSN: 2333-9721
APC: Only $99
Paper Submission

ViewsDownloads

Relative Articles

Idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis with bronchogenic carcinoma

Smoking and Idiopathic Pulmonary Fibrosis

Idiopathic Pulmonary Fibrosis in a Child

Treatment of Idiopathic Pulmonary Fibrosis - An unmet clinical need

Pirfenidone treatment of idiopathic pulmonary fibrosis

Lymphatics in lymphangioleiomyomatosis and idiopathic pulmonary fibrosis

Pirfenidone treatment of idiopathic pulmonary fibrosis

Growth factors in idiopathic pulmonary fibrosis: relative roles

A new direction in the pathogenesis of idiopathic pulmonary fibrosis?

More...
PLOS ONE  2012 

Autophagy in Idiopathic Pulmonary Fibrosis

DOI: 10.1371/journal.pone.0041394

Full-Text   Cite this paper   Add to My Lib

Abstract:

Background Autophagy is a basic cellular homeostatic process important to cell fate decisions under conditions of stress. Dysregulation of autophagy impacts numerous human diseases including cancer and chronic obstructive lung disease. This study investigates the role of autophagy in idiopathic pulmonary fibrosis. Methods Human lung tissues from patients with IPF were analyzed for autophagy markers and modulating proteins using western blotting, confocal microscopy and transmission electron microscopy. To study the effects of TGF-β1 on autophagy, human lung fibroblasts were monitored by fluorescence microscopy and western blotting. In vivo experiments were done using the bleomycin-induced fibrosis mouse model. Results Lung tissues from IPF patients demonstrate evidence of decreased autophagic activity as assessed by LC3, p62 protein expression and immunofluorescence, and numbers of autophagosomes. TGF-β1 inhibits autophagy in fibroblasts in vitro at least in part via activation of mTORC1; expression of TIGAR is also increased in response to TGF-β1. In the bleomycin model of pulmonary fibrosis, rapamycin treatment is antifibrotic, and rapamycin also decreases expression of á-smooth muscle actin and fibronectin by fibroblasts in vitro. Inhibition of key regulators of autophagy, LC3 and beclin-1, leads to the opposite effect on fibroblast expression of á-smooth muscle actin and fibronectin. Conclusion Autophagy is not induced in pulmonary fibrosis despite activation of pathways known to promote autophagy. Impairment of autophagy by TGF-β1 may represent a mechanism for the promotion of fibrogenesis in IPF.

 References

[1]  Ashford TP, Porter KR (1962) Cytoplasmic components in hepatic cell lysosomes. J Cell Biol 12: 198–202.
[2]  Klionsky DJ, Emr SD (2000) Autophagy as a regulated pathway of cellular degradation. Science 290: 1717–1721.
[3]  Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, et al. (2004) The role of autophagy during the early neonatal starvation period. Nature 432: 1032–1036.
[4]  Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, et al. (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441: 880–884.
[5]  Nakai A, Yamaguchi O, Takeda T, Higuchi Y, Hikoso S, et al. (2007) The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med 13: 619–624.
[6]  Kundu M, Thompson CB (2008) Autophagy: basic principles and relevance to disease. Annu Rev Pathol 3: 427–455.
[7]  Levine B, Abrams J (2008) p53: The Janus of autophagy? Nat Cell Biol 10: 637–639.
[8]  Chen ZH, Kim HP, Sciurba FC, Lee SJ, Feghali-Bostwick C, et al. (2008) Egr-1 regulates autophagy in cigarette smoke-induced chronic obstructive pulmonary disease. PLoS One 3: e3316.
[9]  Hwang JW, Chung S, Sundar IK, Yao H, Arunachalam G, et al. (2010) Cigarette smoke-induced autophagy is regulated by SIRT1-PARP-1-dependent mechanism: implication in pathogenesis of COPD. Arch Biochem Biophys 500: 203–209.
[10]  Monick MM, Powers LS, Walters K, Lovan N, Zhang M, et al. (2010) Identification of an autophagy defect in smokers' alveolar macrophages. J Immunol 185: 5425–5435.
[11]  Luciani A, Villella VR, Esposito S, Brunetti-Pierri N, Medina D, et al. (2010) Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition. Nat Cell Biol 12: 863–875.
[12]  Parkhitko A, Myachina F, Morrison TA, Hindi KM, Auricchio N, et al. (2011) Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent. Proc Natl Acad Sci U S A 108: 12455–12460.
[13]  Mi S, Li Z, Yang HZ, Liu H, Wang JP, et al. (2011) Blocking IL-17A promotes the resolution of pulmonary inflammation and fibrosis via TGF-beta1-dependent and -independent mechanisms. J Immunol 187: 3003–3014.
[14]  Korfei M, Ruppert C, Mahavadi P, Henneke I, Markart P, et al. (2008) Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 178: 838–846.
[15]  Lawson WE, Cheng DS, Degryse AL, Tanjore H, Polosukhin VV, et al. (2011) Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs. Proc Natl Acad Sci U S A 108: 10562–10567.
[16]  Yorimitsu T, Nair U, Yang Z, Klionsky DJ (2006) Endoplasmic reticulum stress triggers autophagy. J Biol Chem 281: 30299–30304.
[17]  Ogata M, Hino S, Saito A, Morikawa K, Kondo S, et al. (2006) Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26: 9220–9231.
[18]  Ding WX, Ni HM, Gao W, Hou YF, Melan MA, et al. (2007) Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival. J Biol Chem 282: 4702–4710.
[19]  Kliment CR, Oury TD (2010) Oxidative stress, extracellular matrix targets, and idiopathic pulmonary fibrosis. Free Radic Biol Med 49: 707–717.
[20]  Kiffin R, Bandyopadhyay U, Cuervo AM (2006) Oxidative stress and autophagy. Antioxid Redox Signal 8: 152–162.
[21]  Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, et al. (2007) Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J 26: 1749–1760.
[22]  Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, et al. (2008) Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 283: 10892–10903.
[23]  Tzouvelekis A, Harokopos V, Paparountas T, Oikonomou N, Chatziioannou A, et al. (2007) Comparative expression profiling in pulmonary fibrosis suggests a role of hypoxia-inducible factor-1alpha in disease pathogenesis. Am J Respir Crit Care Med 176: 1108–1119.
[24]  Zhou G, Dada LA, Wu M, Kelly A, Trejo H, et al. (2009) Hypoxia-induced alveolar epithelial-mesenchymal transition requires mitochondrial ROS and hypoxia-inducible factor 1. Am J Physiol Lung Cell Mol Physiol 297: L1120–1130.
[25]  Lu Y, Azad N, Wang L, Iyer AK, Castranova V, et al. (2010) Phosphatidylinositol-3-kinase/akt regulates bleomycin-induced fibroblast proliferation and collagen production. Am J Respir Cell Mol Biol 42: 432–441.
[26]  Lee M, Hwang JT, Lee HJ, Jung SN, Kang I, et al. (2003) AMP-activated protein kinase activity is critical for hypoxia-inducible factor-1 transcriptional activity and its target gene expression under hypoxic conditions in DU145 cells. J Biol Chem 278: 39653–39661.
[27]  Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y (2004) In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 15: 1101–1111.
[28]  Mizushima N, Yoshimori T, Levine B (2010) Methods in mammalian autophagy research. Cell 140: 313–326.
[29]  Zhang HY, Gharaee-Kermani M, Zhang K, Karmiol S, Phan SH (1996) Lung fibroblast alpha-smooth muscle actin expression and contractile phenotype in bleomycin-induced pulmonary fibrosis. Am J Pathol 148: 527–537.
[30]  Kang HR, Lee CG, Homer RJ, Elias JA (2007) Semaphorin 7A plays a critical role in TGF-beta1-induced pulmonary fibrosis. J Exp Med 204: 1083–1093.
[31]  Klionsky DJ, Cuervo AM, Seglen PO (2007) Methods for monitoring autophagy from yeast to human. Autophagy 3: 181–206.
[32]  Wu L, Derynck R (2009) Essential role of TGF-beta signaling in glucose-induced cell hypertrophy. Dev Cell 17: 35–48.
[33]  Orvedahl A, Levine B (2009) Eating the enemy within: autophagy in infectious diseases. Cell Death Differ 16: 57–69.
[34]  Chang YP, Tsai CC, Huang WC, Wang CY, Chen CL, et al. (2010) Autophagy facilitates IFN-gamma-induced Jak2-STAT1 activation and cellular inflammation. J Biol Chem 285: 28715–28722.
[35]  Bjornsti MA, Houghton PJ (2004) The TOR pathway: a target for cancer therapy. Nat Rev Cancer 4: 335–348.
[36]  Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, et al. (2006) TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126: 107–120.
[37]  Bensaad K, Cheung EC, Vousden KH (2009) Modulation of intracellular ROS levels by TIGAR controls autophagy. EMBO J 28: 3015–3026.
[38]  Poulalhon N, Farge D, Roos N, Tacheau C, Neuzillet C, et al. (2006) Modulation of collagen and MMP-1 gene expression in fibroblasts by the immunosuppressive drug rapamycin. A direct role as an antifibrotic agent? J Biol Chem 281: 33045–33052.
[39]  Rahimi RA, Andrianifahanana M, Wilkes MC, Edens M, Kottom TJ, et al. (2009) Distinct roles for mammalian target of rapamycin complexes in the fibroblast response to transforming growth factor-beta. Cancer Res 69: 84–93.
[40]  Goc A, Choudhary M, Byzova TV, Somanath PR (2011) TGFbeta- and bleomycin-induced extracellular matrix synthesis is mediated through Akt and mammalian target of rapamycin (mTOR). J Cell Physiol 226: 3004–3013.
[41]  Kang Y, Chen CR, Massague J (2003) A self-enabling TGFbeta response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial cells. Mol Cell 11: 915–926.
[42]  Lin L, Zhou Z, Zheng L, Alber S, Watkins S, et al. (2008) Cross talk between Id1 and its interactive protein Dril1 mediate fibroblast responses to transforming growth factor-beta in pulmonary fibrosis. Am J Pathol 173: 337–346.
[43]  Jung CH, Ro SH, Cao J, Otto NM, Kim DH (2010) mTOR regulation of autophagy. FEBS Lett 584: 1287–1295.
[44]  Korfhagen TR, Le Cras TD, Davidson CR, Schmidt SM, Ikegami M, et al. (2009) Rapamycin prevents transforming growth factor-alpha-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 41: 562–572.
[45]  Simler NR, Howell DC, Marshall RP, Goldsack NR, Hasleton PS, et al. (2002) The rapamycin analogue SDZ RAD attenuates bleomycin-induced pulmonary fibrosis in rats. Eur Respir J 19: 1124–1127.
[46]  Tulek B, Kiyan E, Toy H, Kiyici A, Narin C, et al. (2011) Anti-inflammatory and anti-fibrotic effects of sirolimus on bleomycin-induced pulmonary fibrosis in rats. Clin Invest Med 34: E341.
[47]  Yoshizaki A, Yanaba K, Iwata Y, Komura K, Ogawa F, et al. (2010) Treatment with rapamycin prevents fibrosis in tight-skin and bleomycin-induced mouse models of systemic sclerosis. Arthritis Rheum 62: 2476–2487.
[48]  Aranguiz-Urroz P, Canales J, Copaja M, Troncoso R, Vicencio JM, et al. (2011) Beta(2)-adrenergic receptor regulates cardiac fibroblast autophagy and collagen degradation. Biochim Biophys Acta 1812: 23–31.
[49]  Kim SI, Na HJ, Ding Y, Wang Z, Lee SJ, et al. (2012) Autophagy Promotes Intracellular Degradation of Type I Collagen Induced by Transforming Growth Factor (TGF)-beta1. J Biol Chem 287: 11677–11688.
[50]  Hoyer-Hansen M, Jaattela M (2007) Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death Differ 14: 1576–1582.
[51]  Lawson WE, Crossno PF, Polosukhin VV, Roldan J, Cheng DS, et al. (2008) Endoplasmic reticulum stress in alveolar epithelial cells is prominent in IPF: association with altered surfactant protein processing and herpesvirus infection. Am J Physiol Lung Cell Mol Physiol 294: L1119–1126.
[52]  Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149: 274–293.
[53]  Fu L, Sztul E (2009) ER-associated complexes (ERACs) containing aggregated cystic fibrosis transmembrane conductance regulator (CFTR) are degraded by autophagy. Eur J Cell Biol 88: 215–226.

Full-Text

comments powered by Disqus