Idiopathic Pulmonary Fibrosis, Opportunities and ...

9 downloads 0 Views 300KB Size Report
Abstract: Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive and fatal disease. The average survival time has a range between 2 to 5 years, but the ...
Send Orders for Reprints to [email protected] Clinical Anti-Inflammatory & Anti-Allergy Drugs, 2014, 1, 95-98

95

Idiopathic Pulmonary Fibrosis, Opportunities and Challenges Glenda Ernsta,*, Borsini Eduardoa and Salvado Alejandroa a

Hospital Británico, Buenos Aires, Argentina Abstract: Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive and fatal disease. The average survival time has a range between 2 to 5 years, but the progression rate and the size of damage could result unpredictable. This fibrotic illness is limited to lung with low or absent inflammation. Recently, new therapeutic options have been described. Clinical trials were not powered to detect statistically significant differences in mortality; but these have shown a reduction in the rate of decline in lung function. The results remain variables due to the heterogeneity observed in these patients. The challenge is to discover new predicting outcomes, biological indicators of disease progression, short-term measures of therapeutic response or predictors of survival time useful to take decisions about the treatment or help to determine the need of lung transplantation and contribute to it.

Keywords: Biomarkers, heterogeneity, idiopathic pulmonary fibrosis, myofibroblast, translational research. 1. INTRODUCTION Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive and fatal disease which affects adult subjects between 60 and 75 years old [1]. The average survival time has a range between 2 to 5 years since diagnosis, however the progression rate and the size of damage could result unpredictable [2, 3]. Annual incidence is estimated between 6 and 16/100.00 subjects, and the prevalence between 13 and 20/100.000. This illness is more common in male and their frequency increases with the age [4, 5]. In contrast with cancer, IPF has been limited to the lung. Despite the efforts, treatments for patients with IPF have showed low effectiveness to improve the course of this disease [6]. At the beginning, the IPF clinical presentation consists of progressive dyspnoea with dry cough and bibasilar inspiratory crackles (velcro crackles). The disease progresses towards chronic restrictive respiratory failure and death. Although most of the patients die from a progressive respiratory failure, *Address correspondence to this author at the Perdriel 74, P.O. Box: C1280AEB, Ciudad Autónoma de Buenos Aires, Argentina; Tel/Fax: +54-11-43096400; E-mail: [email protected] 2212-7046/14 $58.00+.00

possibility to predict outcomes is a challenge due to the heterogeneity of disease progression [7]. Genetic variant has been described in familiar IPF: mutation in the promoter of a mucin called MUC-5 [8] and mutation in TOLLIP or SPPL2C have been characterized [9]. Despite this evidence, gene therapy is not a treatment of choice. Several risk factors would be related with the IPF. Cigarette is one the most important, followed by wood or metal dust [10]. Most of the patients show gastroesophagic reflux and it has been demonstrated that the chronic miscroaspirations could be secondary associated with the development of IPF [11]. What is more, the miscroaspirations have been proposed as one possible mechanism leading to the acute exacerbations in IPF patients [12]. However, pepsin levels were not a clinical exacerbations predictor. 1.1. Mechanisms Involved in the Development of IPF IPF is characterized as a fibro-proliferative disease with an excessive collagen deposition and extracellular matrix (ECM) in the lung parenchyma as a consequence of activation and proliferation of lung fibroblast. Analyses of lung biop© 2014 Bentham Science Publishers

96 Clinical Anti-Inflammatory & Anti-Allergy Drugs, 2014, Vol. 1, No. 2

Ernst et al.

sies show the coexistence of normal and fibrosis area with fibroblastic foci [13]. It has been described that cellular and molecular mechanisms are involved in the development of IPF, but some of the pathways that lead to fibrosis remain unclear. New studies to improve the understanding of these mechanisms could potentially contribute to new therapeutic targets.

increased permeability of vascular endothelium resulting in capillary leakage of fibrinogen, and deposition of fibrin clots into the interstitial and alveolar spaces triggering several pro-fibrotic mechanisms. The resolution of the fibrin matrix at the alveolar space favors the restoration of alveolar haemostasis, however, IFP is usually associated with a deficient function of alveolar fibrinolysis [26]. The fibronectin and fibrin deposits in the underlying fibroblastic foci area would be associated with mesenchymal epithelial differentiation, even in the absence of transforming growth factor beta (TGF-) [27]. Moreover, thrombin and factor X contribute to activate kinase-proteins related with the activation and differentiation of miofibroblastos [28, 29].

Cellular mediators IPF is a disease perpetuated by aberrant wound healing, rather than primarily by chronic inflammation and is typically characterized by established fibrosis with architectural destruction of the lung and loss of gas exchange surface area [14]. The injury of alveolar epithelial cells type 2 is an early feature from IPF patients; this could be a key of the aberrant wound healing response and pathogenesis of the disease [15-17]. However, the major cell that drives fibrosis is the myofibroblast [18]. These cells accumulate in the fibroblast foci and contribute with the synthesis of extracellular matrix (ECM) proteins, leading to tissue remodeling [19, 20]. Understanding the cellular mechanisms that lead fibroblast to myofibroblast transition and then myofibroblast proliferation would be the clue in the regulation of the fibrotic processes. The healing process, usually involves the recruitment and proliferation of fibroblasts to the site where the injury occurred. Proliferation rate and activation of fibroblast are regulated by a dual stimulus; tumor growth factor (TGF-) and a particular isoform of fibronectin demonstrated the major role of extracellular matrix in fibrotic process [21, 22]. Different sources of myofibroblast have been described: activation of resident fibroblast; mesenchymal-epithelial trans-differentiation and circulating fibrocytes. Moeller A. et al. have reported that an increase in the circulating fibrocytes, could be related with a poor prognosis in patients with IPF; but the particular role of fibrocytes in the fibrosis process remain unclear [2325]. Role of Factors of the Coagulation Cascade It has been previously described that some factors of the coagulation cascade may be involved in the development of fibrosis. Lung injury induces

1.2. Biomarkers It has been previously reported that the role of biomarkers is associated with the progression of the IPF. The mucin, KL-6 was found to be significantly increased in serum samples from patients with IPF. Yokoyama and his colleges demonstrated correlation between serum levels of KL-6 with lower survival of patients [30]. Gilani et al. have shown functional alteration in cellular blood population; they described a significant increase of CD4-CD28low lymphocytes in IPF patients. Moreover, they described a relationship between the increase of cells CD4-CD28low and a worse clinical status of IPF patients [31]. CONCLUSION IPF is a complex disease; the mechanism that leads the fibrotic process remains unclear. Currently, categorizing of the patients with IPF is based on clinical data. There is a need to identify phenotypes or clusters to predict the rate of progression or the response to a possible treatment. The successful development of useful biomarkers is a challenge for the future of translational research in IPF. LIST OF ABBREVIATIONS IPF

= Idiopathic pulmonary fibrosis

TGF

= Transforming growth factor 

ECM

= Extracellular matrix

Idiopathic Pulmonary Fibrosis, Opportunities and Challenges

Clinical Anti-Inflammatory & Anti-Allergy Drugs, 2014, Vol. 1, No. 2

CONFLICT OF INTEREST

[14]

The author(s) confirm that this article content has no conflict of interest.

[15]

ACKNOWLEDGEMENTS Declared none. REFERENCES [1]

[2]

[3]

[4] [5] [6]

[7]

[8] [9]

[10] [11]

[12]

[13]

Raghu G, Weycker D, Edelsberg J, Bradford WZ and Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2006; 174: 810-6. Gribbin J, Hubbard RB, Le Jeune I, Smith CJ, West J, Tata LJ. Incidence and mortality of idiopathic pulmonary fibrosis and sarcoidosis in the UK. Thorax 2006; 61: 980-5. Song JW, Hong SB, Lim CM, Koh Y, Kim DS. Acute exacerbation of idiopathic pulmonary fibrosis: Incidence, risk factors and outcome. Eur Respir J 2011; 37: 356-63. Nathan SD, Du Bois RM. Idiopathic pulmonary fibrosis trials: Recommendations for the jury. Eur Respir J 2011; 38: 1002-4. Maher TM. Disease stratification in idiopathic pulmonary fibrosis: the dawn of a new era? Eur Respir J 2014; 43(5): 1233-6. Vancheri C, Failla M, Crimi N, Raghu G. Idiopathic pulmonary fibrosis: A disease with similarities and links to cancer biology. Eur Respir J 2010; 35: 496504. Raghu G, Collard HR, Egan JJ, et al. An Official ATS/ERS/ JRS/ALAT statement: Idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183: 788-824. Seibold MA, Wise AL, Speer MC, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med 2011; 364: 1503-12. Noth I, Zhang Y, Ma SF, et al. Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: A genome-wide association study. Lancet Respir Med 2013; 1: 309-17. King TE Jr, Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet 2011; 378:1949-61. Lee JS, Ryu JH, Elicker BM, et al. Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011; 184: 1390-4. Lee JS, Song JW, Wolters PJ, et al. Bronchoalveolar lavage pepsin in acute exacerbation of idiopathic pulmonary fibrosis. Eur Respir J 2012; 39(2): 352-8. Maher TM. Beyond the diagnosis of idiopathic pulmonary fibrosis; the growing role of systems biology and stratified medicine. Curr Opin Pulm Med 2013; 19: 460-5.

[16]

[17]

[18] [19] [20]

[21]

[22]

[23]

[24] [25]

[26]

[27] [28]

[29]

97

King TE Jr, Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet 2011; 378: 1949-61. Plataki M, Koutsopoulos AV, Darivianaki K, Delides G, Siafakas NM, Bouros D. Expression of apoptotic and antiapoptotic markers in epithelial cells in idiopathic pulmonary fibrosis. Chest 2005; 127: 266-74. Barkauskas CE, Noble PW. Cellular mechanisms of tissue fibrosis. New insights into the cellular mechanisms of pulmonary fibrosis. Am J Physiol Cell Physiol 2014; 306(11): C987-96. Sisson TH, Mendez M, Choi K, et al. Targeted injury of type II alveolar epithelial cells induces pulmonary fibrosis. Am J Respir Crit Care Med; 2010; 181: 25463. Lekkerkerker AN, Aarbiou J, Van Es T, Janssen RA. Cellular players in lung fibrosis. Curr Pharm Des 2012; 18(27): 4093-02. Duffield JS, Lupher M, Thannickal VJ, Wynn TA. Host responses in tissue repair and fibrosis. Annu Rev Pathol 2013; 8: 241-76. Kramann R, DiRocco DP, Humphreys BD. Understanding the origin, activation and regulation of matrix-producing myofibroblasts for treatment of fibrotic disease. J Pathol 2013; 231(3): 273-89. Desmouliere A, Geinoz A, Gabbiani F, Gabbiani G. Transforming growth factor-1 induces -smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol 1993; 122: 103-11. Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 2002; 3: 349-63. Kramann R, DiRocco DP, Humphreys BD. Understanding the origin, activation and regulation of matrix-producing myofibroblasts for treatment of fibrotic disease. J Pathol 2013; 3: 273-89. Reilkoff RA, Bucala R, Herzog EL. Fibrocytes: Emerging effector cells in chronic inflammation. Nat Rev Immunol 2011; 11: 427-35. Moeller A, Gilpin SE, Ask K, et al. Circulating fibrocytes are an indicator of poor prognosis in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2009; 179: 588-94. Bhandary YP, Shetty SK, Marudamuthu AS, et al. Regulation of alveolar epithelial cell apoptosis and pulmonary fibrosis by coordinate expression of components of the fibrinolytic system. Am J Physiol Lung Cell Mol Physiol 2012; 302: L463-73. Chambers RC1, Scotton CJ. Coagulation cascade proteinases in lung injury and fibrosis. Proc Am Thorac Soc 2012; 9(3): 96-01. Scotton CJ, Krupiczojc MA, Konigshoff M, et al. Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury. J Clin Invest 2009; 119: 2550-63. Bogatkevich GS, Tourkina E, Silver RM, LudwickaBradley A. Thrombin differentiates normal lung fibroblasts to a myofibroblast phenotype via the proteolytically activated receptor-1 and a protein

98 Clinical Anti-Inflammatory & Anti-Allergy Drugs, 2014, Vol. 1, No. 2

[30]

kinase C-dependent pathway. J Biol Chem 2001; 276: 45184-19. Yokoyama A, Kondo K, Nakajima M, et al. Prognostic value of circulating KL-6 in idiopathic pulmonary fibrosis. Respirology 2006; 11: 164-8.

Received: December 20, 2014

Revised: January 02, 2015

Accepted: January 06, 2015

Ernst et al.

[31]

Gilani SR, Vuga LJ, Lindell KO, et al. CD28 down-regulation on circulating CD4 T-cells is associated with poor prognoses of patients with idiopathic pulmonary fibrosis. PLoS One 2010; 5(1): e8959.