Final Report Summary - EURIPFNET (European IPF Network: Natural course, pathomechanisms and novel treatment options in idiopathic pulmonary fibrosis)
EURIPFNET was funded under the Seventh Framework Programme (FP7) from 1 January 2008 until 30 June 2011. In this consortium, leading European basic and clinical scientists work together to jointly decipher the natural course and molecular pathomechanisms of idiopathic pulmonary fibrosis (IPF) and to develop new therapeutic strategies for patients with IPF, a devastating disease with a mean life expectancy of approximately three years after diagnosis, affecting approximately 200 000 patients in Europe.
One of our expressed goals was to cover the entire chain of translational research, from molecular pathway analysis in isolated cells up to bedside evaluation of patients. Following this concept, we established a European IPF registry (EURIPFREG) and a European IPF biobank (EURIPFBANK) (work package (WP)1) that remain fully active and serve as precious and steadily growing data and biomaterial repository for future research in IPF. Meanwhile, several site investigators from all over Europe have joined this registry / biobank. Based on this registry / biobank, we were able to conduct extensive non-hypothesis driven transcriptome, proteome and lipidome analyses (WP2), which forwarded important and new insights into potential disease triggers and mechanisms.
Thorough analyses of consecutive interactions between growth factors or proteases and cell-surface receptors, downstream signalling pathways and cellular plasticity was undertaken in WP3; largely on the basis of loss-of-function / gain-of-function experiments in specific pulmonary cell types in vitro and in vivo. In WP4, we aimed to develop and establish novel animal models of IPF, aiming to reproduce proposed trigger mechanisms as outlined in WP2. As a result of these activities we were able to establish two novel models based on transtracheal application of amiodarone and pepstatin and one model based on a combined genotype of naturally occurring mutations (Hermansky-Pudlak syndrome genes 1 and 2). Other, genetically engineered mice are still in the process of being phenotyped and may also develop lung fibrosis. Making use of these novel models, we investigated a series of different therapeutic agents (WP5), aiming to either block the initial trigger event or consecutive fibroproliferative pathways. Some of these compounds studied in the frame of the EURIPFNET are currently under further preclinical investigation for putative treatment of IPF.
Finally, in WP6, we aimed at establishing better disease-specific markers as well as markers of disease activity, the future use of which may facilitate correct diagnosis of IPF or early evaluation of drug efficacy. In this regard, the peripheral blood cell transcriptome of IPF has been fully established and compared to age matched healthy individuals, as well as other pulmonary disease categories. Taken together, the EURIPFNET has been extremely successful not only in providing durable research structures and models for the future, but also in deciphering initial triggering processes, consecutive pro-fibrotic signalling events and novel therapeutic agents for IPF.
Based on the results and generated data produced during the time span of FP7 funding, we have contributed valuable advancement to IPF research, true to our mission statement: fighting for improved survival in IPF.
Project context and objectives:
IPF is a life-threatening and devastating disease, for which no cure exists at the moment. Although epidemiological data are scarce, the prevalence of IPF has been reported to range between 20.2 / 100 000 (men) and 13.2 / 100 000 (women) and the incidence between 10.7 / 100 000 (men) and 7.4 / 100 000 (women) in a population based study in New Mexico, United States (Coultas R. E. et al., Am J Respir Crit Care Med, 150:967, 1994). Concerning Europe, IPF was found to account for approximately 20-30 % of all ILD cases (Schweisfurth H. et al., Pneumologie, 57:373, 2003) and a prevalence rate of 16-18 / 100 000 was reported (Hodgson U. et al., Thorax, 57:338, 2002). Hence, there are probably 200 000 patients with IPF living in the European Union (EU).
IPF is a disease of the middle-aged and affects men slightly more frequently than women. Smoking has been identified as potential risk factor. In approximately 10-15 % of all cases, a familiar background of IPF can be documented, although the underlying molecular mechanisms and involved genes are largely unknown. Patients with IPF usually complain about exertional dyspnoea, later dyspnoea at rest, alongside with a dry cough that may be aggravated or induced by physical exercise (American Thoracic Society / European Respiratory Society, Am J Respir Crit Care Med, 165:277, 2002).
The clinical course is characterised by a progressive decline in exercise capacity, impairment in lung function and loss of quality of life. Patients are getting increasingly dependent on long-term oxygen treatment. Intercurrent respiratory infections seem not only to frequently antecede the first symptoms; they are also very frequent thereafter and seem to aggravate the clinical course. The average life expectancy of IPF patients upon first diagnosis still ranges only between 2-3 years (Schwartz D. A. et al., Am J Respir Crit Care Med, 149:450, 1994), with lung transplantation being the most promising, although imperfect and inconsistently realised treatment option. Not unexpectedly, the socioeconomic burden of the disease is assumed to be high.
On the basis of this disheartening outlook for IPF patients, the European IPF network was born in 2008, aiming at combining the basic and translational research efforts of different European entities to permanently improve the scientific infrastructure that will allow for a better understanding of IPF.
One of the major problems in IPF research is the scarcity of available data and reliable information on pathomechanisms of the disease, as well as availability of sufficient biomaterials for innovative research activities. In our network, five European countries have combined their forces to extend the knowledge base and improve patient care for patients with IPF. In creating our network of EURIPFNET consortium partners, we were able to combine five leading IPF patient recruitment centres in Europe (University of Giessen Lung Center, Royal Brompton Hospital London, University of Catania, Inserm Paris and INSERM Dijon) with matching basic science strength on site and at additional institutions (University College London, University Hospital Regensburg, General Hospital Vienna, LIMES Bonn and Helmholtz Center Munich). Our initial research goals were divided in 6 major research projects combined with an administrative core located at the coordinator's home institution in Giessen, Germany.
WP1 'EURIPFREG and EURIPFBANK' encompasses the core of our future knowledge base. Through the establishment of a comprehensive data and biobank, we create a gateway for insightful patient data analysis and biomaterial analysis.
WP2 'Elucidation of triggering events and early cellular responses' aims to identify and verify new trigger events, their signal transduction pathways as well as the early cellular response pattern in IPF; a prerequisite for the work performed in WP4 'Development of new animal models of IPF'.
WP3 'Growth factor response, matrix regulation and cell-cell interaction' elucidates humoral and cellular response patterns that underlie the progressive fibrotic response towards an initial injury in IPF.
WP5 'Preclinical evaluation of new therapeutic strategies in IPF' makes use of the data and biomaterial gathered in the frame of WP1 modalities preclinically.
And, finally, WP6 'Identification of disease-specific markers and surrogate markers of disease progression' focuses on the identification of novel-disease specific markers and surrogate parameters of disease progression, hoping for improved IPF patient identification and subsequent increased efficacy in treatment.
Within these work packages the following main objectives were defined:
- Implementation of a EURIPFREG, open to all clinical experts in the EU. The goal of EURIPFREG was to gather valuable, reviewed and centrally approved data with regard to natural course, familiar background and susceptibility factors of IPF.
- Setup of EURIPFBANK, in which blood, bronchoalveolar lavage fluid, cells and tissue specimen of IPF subjects are collected and kept in trust.
- Description of IPF-specific transcriptome, proteome, phosphoproteome and lipidome profiles in lung tissue and circulating peripheral blood cells to unravel the molecular pathways and signalling pathways underlying initiation and progression of IPF.
- Identification and verification of molecular events and genes triggering IPF.
- Definition of key changes in cellular interactions and description of the hierarchy of involved growth factors, integrins and proteases involved in the secondary fibrotic response to the trigger.
- Identification of new animal models that better mimic the natural course of IPF as compared to the currently available models.
- Identification and preclinical evaluation of new therapeutic compounds for treatment of IPF.
- Evaluation of non-invasive, exhaled breath based, surrogate parameters of disease activity and identification of new diagnostic and prognostic markers.
With every step in the individual research efforts, methods in our laboratories were improved and adapted to address new findings and to overcome unforeseen hurdles and come closer to understanding the pathomechanisms of IPF.
Project results:
Since the initiation of EURIPFNET in 2008 all major scientific goals of the consortium have been met:
- A EURIPFNET webpage has been setup to serve the needs of patients, physicians and scientists interested and involved in the topic of IPF research (please see http://www.pulmonary-fibrosis.net online). On this webpage, relevant information on the disease itself, the participating scientists and the goals of the consortium are displayed and updated on a regular basis. The webpage also serves as a communication platform for involved scientists and as the portal for the EURIPFREG.
- EURIPFREG and EURIPFBANK have been developed and improved based on the most recent and relevant guidelines in the EU. All relevant patient / physician documents of EURIPFREG as well as the data protection concept and site investigator contracts are approved in their current form by local or national ethical committees (Austria, Germany, Czech Republic, France, Hungary, Italy, Spain and the UK). The registry is open to all clinical experts in the EU and allows collection of data on the natural course, familial background and susceptibility factors of IPF. Alongside with the clinical data, biomaterials (blood, bronchoalveolar lavage fluid, cells and tissue specimen) from IPF patients are collected and are kept in trust in the EURIPFBANK. An additional function has been created to include other lung diseases as control groups for EURIPFREG. By the end of the FP7 funding period EURIPFREG hosted data sets for over 300 patients, to date the registry contains data for 650 patients.
- The IPF-specific transcriptome, lipidome and proteome have been identified and important molecular and signalling pathways underlying the disease have been disclosed. A detailed analysis of certain pathways employing in vitro and in vivo experiments resulted in a better understanding of mechanistic principles underlying IPF and identified a novel target for therapeutic intervention in pulmonary fibrosis. We evidently confirmed the signature of a chronic Endoplasmic reticulum (ER) stress-response in the alveolar epithelium, paralleled by signatures of enhanced infection susceptibility, depletion of enzymatic antioxidants and deterioration of alveolar structure, along with marked upregulation of markers reflecting aberrant epithelial proliferation / repair and bronchiolisation.
- Some recent data on novel pathways provided information on a potential role of the Wnt and notch signalling pathways in maintenance of the differentiation state and proliferation of the alveolar epithelium, which seems to be important for regeneration of the alveolar epithelium in the lung.
- Novel animal models of IPF, which have been developed to more adequately mimic the clinical course of IPF, have been intensively characterised. In particular, the amiodarone model allowed us to identify new mechanistic aspects, which are also effective in lungs from IPF patients. The HPS 1 / 2 model has been further developed and represents a suitable, genetically based model of IPF.
- Likewise, novel therapeutic compounds, designed and produced by this consortium have been analysed in standard and new animal models of lung fibrosis.
- Finally, using peripheral blood cells, an IPF-specific transcriptome was identified that can be applied to reliably discriminate IPF patients from control patients. This approach largely contributes to an improvement in diagnosis of IPF and may also be useful for prognostic purposes.
List of websites: http://www.pulmonary-fibrosis.net
One of our expressed goals was to cover the entire chain of translational research, from molecular pathway analysis in isolated cells up to bedside evaluation of patients. Following this concept, we established a European IPF registry (EURIPFREG) and a European IPF biobank (EURIPFBANK) (work package (WP)1) that remain fully active and serve as precious and steadily growing data and biomaterial repository for future research in IPF. Meanwhile, several site investigators from all over Europe have joined this registry / biobank. Based on this registry / biobank, we were able to conduct extensive non-hypothesis driven transcriptome, proteome and lipidome analyses (WP2), which forwarded important and new insights into potential disease triggers and mechanisms.
Thorough analyses of consecutive interactions between growth factors or proteases and cell-surface receptors, downstream signalling pathways and cellular plasticity was undertaken in WP3; largely on the basis of loss-of-function / gain-of-function experiments in specific pulmonary cell types in vitro and in vivo. In WP4, we aimed to develop and establish novel animal models of IPF, aiming to reproduce proposed trigger mechanisms as outlined in WP2. As a result of these activities we were able to establish two novel models based on transtracheal application of amiodarone and pepstatin and one model based on a combined genotype of naturally occurring mutations (Hermansky-Pudlak syndrome genes 1 and 2). Other, genetically engineered mice are still in the process of being phenotyped and may also develop lung fibrosis. Making use of these novel models, we investigated a series of different therapeutic agents (WP5), aiming to either block the initial trigger event or consecutive fibroproliferative pathways. Some of these compounds studied in the frame of the EURIPFNET are currently under further preclinical investigation for putative treatment of IPF.
Finally, in WP6, we aimed at establishing better disease-specific markers as well as markers of disease activity, the future use of which may facilitate correct diagnosis of IPF or early evaluation of drug efficacy. In this regard, the peripheral blood cell transcriptome of IPF has been fully established and compared to age matched healthy individuals, as well as other pulmonary disease categories. Taken together, the EURIPFNET has been extremely successful not only in providing durable research structures and models for the future, but also in deciphering initial triggering processes, consecutive pro-fibrotic signalling events and novel therapeutic agents for IPF.
Based on the results and generated data produced during the time span of FP7 funding, we have contributed valuable advancement to IPF research, true to our mission statement: fighting for improved survival in IPF.
Project context and objectives:
IPF is a life-threatening and devastating disease, for which no cure exists at the moment. Although epidemiological data are scarce, the prevalence of IPF has been reported to range between 20.2 / 100 000 (men) and 13.2 / 100 000 (women) and the incidence between 10.7 / 100 000 (men) and 7.4 / 100 000 (women) in a population based study in New Mexico, United States (Coultas R. E. et al., Am J Respir Crit Care Med, 150:967, 1994). Concerning Europe, IPF was found to account for approximately 20-30 % of all ILD cases (Schweisfurth H. et al., Pneumologie, 57:373, 2003) and a prevalence rate of 16-18 / 100 000 was reported (Hodgson U. et al., Thorax, 57:338, 2002). Hence, there are probably 200 000 patients with IPF living in the European Union (EU).
IPF is a disease of the middle-aged and affects men slightly more frequently than women. Smoking has been identified as potential risk factor. In approximately 10-15 % of all cases, a familiar background of IPF can be documented, although the underlying molecular mechanisms and involved genes are largely unknown. Patients with IPF usually complain about exertional dyspnoea, later dyspnoea at rest, alongside with a dry cough that may be aggravated or induced by physical exercise (American Thoracic Society / European Respiratory Society, Am J Respir Crit Care Med, 165:277, 2002).
The clinical course is characterised by a progressive decline in exercise capacity, impairment in lung function and loss of quality of life. Patients are getting increasingly dependent on long-term oxygen treatment. Intercurrent respiratory infections seem not only to frequently antecede the first symptoms; they are also very frequent thereafter and seem to aggravate the clinical course. The average life expectancy of IPF patients upon first diagnosis still ranges only between 2-3 years (Schwartz D. A. et al., Am J Respir Crit Care Med, 149:450, 1994), with lung transplantation being the most promising, although imperfect and inconsistently realised treatment option. Not unexpectedly, the socioeconomic burden of the disease is assumed to be high.
On the basis of this disheartening outlook for IPF patients, the European IPF network was born in 2008, aiming at combining the basic and translational research efforts of different European entities to permanently improve the scientific infrastructure that will allow for a better understanding of IPF.
One of the major problems in IPF research is the scarcity of available data and reliable information on pathomechanisms of the disease, as well as availability of sufficient biomaterials for innovative research activities. In our network, five European countries have combined their forces to extend the knowledge base and improve patient care for patients with IPF. In creating our network of EURIPFNET consortium partners, we were able to combine five leading IPF patient recruitment centres in Europe (University of Giessen Lung Center, Royal Brompton Hospital London, University of Catania, Inserm Paris and INSERM Dijon) with matching basic science strength on site and at additional institutions (University College London, University Hospital Regensburg, General Hospital Vienna, LIMES Bonn and Helmholtz Center Munich). Our initial research goals were divided in 6 major research projects combined with an administrative core located at the coordinator's home institution in Giessen, Germany.
WP1 'EURIPFREG and EURIPFBANK' encompasses the core of our future knowledge base. Through the establishment of a comprehensive data and biobank, we create a gateway for insightful patient data analysis and biomaterial analysis.
WP2 'Elucidation of triggering events and early cellular responses' aims to identify and verify new trigger events, their signal transduction pathways as well as the early cellular response pattern in IPF; a prerequisite for the work performed in WP4 'Development of new animal models of IPF'.
WP3 'Growth factor response, matrix regulation and cell-cell interaction' elucidates humoral and cellular response patterns that underlie the progressive fibrotic response towards an initial injury in IPF.
WP5 'Preclinical evaluation of new therapeutic strategies in IPF' makes use of the data and biomaterial gathered in the frame of WP1 modalities preclinically.
And, finally, WP6 'Identification of disease-specific markers and surrogate markers of disease progression' focuses on the identification of novel-disease specific markers and surrogate parameters of disease progression, hoping for improved IPF patient identification and subsequent increased efficacy in treatment.
Within these work packages the following main objectives were defined:
- Implementation of a EURIPFREG, open to all clinical experts in the EU. The goal of EURIPFREG was to gather valuable, reviewed and centrally approved data with regard to natural course, familiar background and susceptibility factors of IPF.
- Setup of EURIPFBANK, in which blood, bronchoalveolar lavage fluid, cells and tissue specimen of IPF subjects are collected and kept in trust.
- Description of IPF-specific transcriptome, proteome, phosphoproteome and lipidome profiles in lung tissue and circulating peripheral blood cells to unravel the molecular pathways and signalling pathways underlying initiation and progression of IPF.
- Identification and verification of molecular events and genes triggering IPF.
- Definition of key changes in cellular interactions and description of the hierarchy of involved growth factors, integrins and proteases involved in the secondary fibrotic response to the trigger.
- Identification of new animal models that better mimic the natural course of IPF as compared to the currently available models.
- Identification and preclinical evaluation of new therapeutic compounds for treatment of IPF.
- Evaluation of non-invasive, exhaled breath based, surrogate parameters of disease activity and identification of new diagnostic and prognostic markers.
With every step in the individual research efforts, methods in our laboratories were improved and adapted to address new findings and to overcome unforeseen hurdles and come closer to understanding the pathomechanisms of IPF.
Project results:
Since the initiation of EURIPFNET in 2008 all major scientific goals of the consortium have been met:
- A EURIPFNET webpage has been setup to serve the needs of patients, physicians and scientists interested and involved in the topic of IPF research (please see http://www.pulmonary-fibrosis.net online). On this webpage, relevant information on the disease itself, the participating scientists and the goals of the consortium are displayed and updated on a regular basis. The webpage also serves as a communication platform for involved scientists and as the portal for the EURIPFREG.
- EURIPFREG and EURIPFBANK have been developed and improved based on the most recent and relevant guidelines in the EU. All relevant patient / physician documents of EURIPFREG as well as the data protection concept and site investigator contracts are approved in their current form by local or national ethical committees (Austria, Germany, Czech Republic, France, Hungary, Italy, Spain and the UK). The registry is open to all clinical experts in the EU and allows collection of data on the natural course, familial background and susceptibility factors of IPF. Alongside with the clinical data, biomaterials (blood, bronchoalveolar lavage fluid, cells and tissue specimen) from IPF patients are collected and are kept in trust in the EURIPFBANK. An additional function has been created to include other lung diseases as control groups for EURIPFREG. By the end of the FP7 funding period EURIPFREG hosted data sets for over 300 patients, to date the registry contains data for 650 patients.
- The IPF-specific transcriptome, lipidome and proteome have been identified and important molecular and signalling pathways underlying the disease have been disclosed. A detailed analysis of certain pathways employing in vitro and in vivo experiments resulted in a better understanding of mechanistic principles underlying IPF and identified a novel target for therapeutic intervention in pulmonary fibrosis. We evidently confirmed the signature of a chronic Endoplasmic reticulum (ER) stress-response in the alveolar epithelium, paralleled by signatures of enhanced infection susceptibility, depletion of enzymatic antioxidants and deterioration of alveolar structure, along with marked upregulation of markers reflecting aberrant epithelial proliferation / repair and bronchiolisation.
- Some recent data on novel pathways provided information on a potential role of the Wnt and notch signalling pathways in maintenance of the differentiation state and proliferation of the alveolar epithelium, which seems to be important for regeneration of the alveolar epithelium in the lung.
- Novel animal models of IPF, which have been developed to more adequately mimic the clinical course of IPF, have been intensively characterised. In particular, the amiodarone model allowed us to identify new mechanistic aspects, which are also effective in lungs from IPF patients. The HPS 1 / 2 model has been further developed and represents a suitable, genetically based model of IPF.
- Likewise, novel therapeutic compounds, designed and produced by this consortium have been analysed in standard and new animal models of lung fibrosis.
- Finally, using peripheral blood cells, an IPF-specific transcriptome was identified that can be applied to reliably discriminate IPF patients from control patients. This approach largely contributes to an improvement in diagnosis of IPF and may also be useful for prognostic purposes.
List of websites: http://www.pulmonary-fibrosis.net