Periodic Reporting for period 4 - XHaLe (Hanover experimental lung research project)
Berichtszeitraum: 2022-12-01 bis 2024-05-31
Assigning diseases to a location within the body and drawing conclusions about etiology and pathogenesis from anatomical changes make up the traditional core method of pathology, originally defined by Rudolph Virchow as „the anatomical concept of pathology“.
Non-neoplastic lung diseases (NNLD), such as COPD and interstitial lung diseases rank second among the causes of death and NNLD appear as a growing challenge for Germany, the EU and worldwide. Viruses are incriminated as exacerbating (co)-factors of fibrotic lung diseases. These are characterized by irreversible fibrotic remodelling with a relentless loss of lung function and a 5-year survival of only 30%. Pulmonary fibrosis results from aberrant injury-repair responses to persistent and / or chronic lung injury. In Xhale, my team and I have dedicated our activities to unravelling the mechanisms of pathogenesis by comprehensively analyzing the cellular and molecular changes that are found in human lung explants and correlating them with morphological and clinical aspects of these diseases. Using these molecular patterns, we were able to better define these diseases and set them apart from each other.
Of special interest in this regard is the question of the origin of these NNLDs. Faced with the Covid-19 pandemic, we were able to demonstrate the initiation of fibrotic remodelling by SARS-CoV-2 infection in humans (Ackermann, et al., 2020, NEJM): vascular damage, angiocentric inflammation and misled angiogenesis, resulted in subsequent pulmonary fibrosis (Jonigk et al., 2020). These findings served as a template for understanding core pathobiological characteristics in NNLD.
Non-neoplastic lung diseases (NNLD), such as COPD and interstitial lung diseases rank second among the causes of death and NNLD appear as a growing challenge for Germany, the EU and worldwide. Viruses are incriminated as exacerbating (co)-factors of fibrotic lung diseases. These are characterized by irreversible fibrotic remodelling with a relentless loss of lung function and a 5-year survival of only 30%. Pulmonary fibrosis results from aberrant injury-repair responses to persistent and / or chronic lung injury. In Xhale, my team and I have dedicated our activities to unravelling the mechanisms of pathogenesis by comprehensively analyzing the cellular and molecular changes that are found in human lung explants and correlating them with morphological and clinical aspects of these diseases. Using these molecular patterns, we were able to better define these diseases and set them apart from each other.
Of special interest in this regard is the question of the origin of these NNLDs. Faced with the Covid-19 pandemic, we were able to demonstrate the initiation of fibrotic remodelling by SARS-CoV-2 infection in humans (Ackermann, et al., 2020, NEJM): vascular damage, angiocentric inflammation and misled angiogenesis, resulted in subsequent pulmonary fibrosis (Jonigk et al., 2020). These findings served as a template for understanding core pathobiological characteristics in NNLD.
XHale provided fundamental insights in the molecular background of NNLDs, their onset, involvement of viruses and their molecular characteristics.
The details of our studies can be found here:
Verleden SE and Jonigk 3d Virtual Pathohistology of Lung Tissue from Covid-19 Patients based on Phase Contrast X-ray Tomography. eLife 2020 Aug 20. doi: 10.7554/elife.60408. (IF 2019: 6.830)
Ackermann M, et al. and Jonigk Pulmonary Vascular Endothelialitis, Thrombosis and Angiogenesis in COVID-19. N Engl J Med. 2020 May 21. doi: 10.1056/NEJMoa2015432. (IF 2019: 70.670)
Ackermann M, et al. and Jonigk Pulmonary Vascular Pathology in Covid-19. Reply. N Engl J Med. 2020 Jul 17. doi: 10.1056/NEJMc2022068. (IF 2019: 70.670)
Neubert L*, at al and Jonigk D#. Molecular Profiling of Vascular Remodeling in Chronic Pulmonary Disease. Am J Pathol. 2020 Apr 7 doi: 10.1016/j.ajpath.2020.03.008 (IF 2017: 4.189)
Ackermann M, et al and Jonigk D. Morphomolecular motifs of pulmonary neoangiogenesis in interstitial lung diseases. Eur Respir J. 2020 Mar 12;55(3):1900933. doi: 10.1183/13993003.00933-2019 (IF 2018: 12,242)
Jonigk D, et al. Morphological and molecular motifs of fibrosing pulmonary injury patterns. J Pathol Clin Res. 2019 doi: 10.1002/cjp2.141. (IF 2015: 7.381)
Neubert L* at al and Jonigk D°. Comprehensive Three-dimensional Morphology of Neoangiogenesis in Pulmonary Veno-occlusive Disease and Pulmonary Capillary Hemangiomatosis. J Pathol Clin Res 2019; 5(2): 108-114. doi: 10.1002/cjp2.125. (IF 2015: 7.381)
Ackermann M et al. A 3D iPSC-differentiation model identifies interleukin-3 as a regulator of early human hematopoietic specification. Haematologica 2020 Apr 23. pii: haematol.2019.228064. doi: 10.3324/haematol.2019.228064 (IF 2018: 7.570)
Ackermann M, et al. Bioreactor-based mass production of human iPSC-derived macrophages enables immunotherapies against bacterial airway infections. Nat Commun 2018; 9(1): 5088. doi: 10.1038/s41467-018-07570-7. (IF 2017: 13.691)
WP 1: "Comprehensive and standardized work-up of explanted human lungs"
This is an ongoing endeavor and the backbone of our work. So far, we were able to include 99% of all lungs transplanted at Hannover Medical School into the Xhale project (113 lungs in 2018, 104 lungs in 2019 and 88 lungs in 2020)
WP 2: "analysis of human lung explants - characterization of the inflammome in NNLDs"
This WP is now a standardized part of our routine workup of lung samples and allowed us great insights into the pathobiology of different NNLDs. We were able to set apart different NNLDs due to their underlying molecular characteristics and provide predictive algorithm that are able to identify a fibrotic pattern with a “90% certainty".
WP 3: From predicted pathomechanisms to certainty - analysis of precision-cut lung slices (PCLS) from explants
The tissue culture of human lung tissue has successfully been established in our lab as a reliable tool for the analysis of NNLD. We successfully cultured pulmonary specimens for 6 weeks and holistically anaöyzed more than 1.000 samples in detail regarding viability of different cell types, gene expression and histology.
The Challenge of Long-Term Cultivation of Human PCLS. Preuß EB et al. Am J Pathol. 2022 Feb;192(2):239-253. doi: 10.1016/j.ajpath.2021.10.020.
Nintedanib modulates collagen turnover in PCLS from fibrosis rats and patients with pulmonary fibrosis. Hesse C…. Respir Res. 2022 Aug 4;23(1):201. doi: 10.1186/s12931-022-02116-4.
Competitive fitness of Pseudomonas aeruginosa isolates in human and murine precision-cut lung slices. Cramer N,… Front Cell Infect Microbiol. 2022 Aug 23;12:992214. doi: 10.3389/fcimb.2022.992214.
WP 4: Molecular investigation of the angiogeneic driver of NNLD remodelling
We analyzed specific vascular changes specifically associated with different forms of fibrotic NNLD remodelling. Intussusceptive neoangiogenesis, which is not only a typical trait of AFE and NSIP, but also of COVID-19 lung pathology, turned out to be involved with the long term complications that SARS-CoV-2 survivors suffer from and it also presents a possible molecular access point for inhibitory therapy.
The details of our studies can be found here:
Verleden SE and Jonigk 3d Virtual Pathohistology of Lung Tissue from Covid-19 Patients based on Phase Contrast X-ray Tomography. eLife 2020 Aug 20. doi: 10.7554/elife.60408. (IF 2019: 6.830)
Ackermann M, et al. and Jonigk Pulmonary Vascular Endothelialitis, Thrombosis and Angiogenesis in COVID-19. N Engl J Med. 2020 May 21. doi: 10.1056/NEJMoa2015432. (IF 2019: 70.670)
Ackermann M, et al. and Jonigk Pulmonary Vascular Pathology in Covid-19. Reply. N Engl J Med. 2020 Jul 17. doi: 10.1056/NEJMc2022068. (IF 2019: 70.670)
Neubert L*, at al and Jonigk D#. Molecular Profiling of Vascular Remodeling in Chronic Pulmonary Disease. Am J Pathol. 2020 Apr 7 doi: 10.1016/j.ajpath.2020.03.008 (IF 2017: 4.189)
Ackermann M, et al and Jonigk D. Morphomolecular motifs of pulmonary neoangiogenesis in interstitial lung diseases. Eur Respir J. 2020 Mar 12;55(3):1900933. doi: 10.1183/13993003.00933-2019 (IF 2018: 12,242)
Jonigk D, et al. Morphological and molecular motifs of fibrosing pulmonary injury patterns. J Pathol Clin Res. 2019 doi: 10.1002/cjp2.141. (IF 2015: 7.381)
Neubert L* at al and Jonigk D°. Comprehensive Three-dimensional Morphology of Neoangiogenesis in Pulmonary Veno-occlusive Disease and Pulmonary Capillary Hemangiomatosis. J Pathol Clin Res 2019; 5(2): 108-114. doi: 10.1002/cjp2.125. (IF 2015: 7.381)
Ackermann M et al. A 3D iPSC-differentiation model identifies interleukin-3 as a regulator of early human hematopoietic specification. Haematologica 2020 Apr 23. pii: haematol.2019.228064. doi: 10.3324/haematol.2019.228064 (IF 2018: 7.570)
Ackermann M, et al. Bioreactor-based mass production of human iPSC-derived macrophages enables immunotherapies against bacterial airway infections. Nat Commun 2018; 9(1): 5088. doi: 10.1038/s41467-018-07570-7. (IF 2017: 13.691)
WP 1: "Comprehensive and standardized work-up of explanted human lungs"
This is an ongoing endeavor and the backbone of our work. So far, we were able to include 99% of all lungs transplanted at Hannover Medical School into the Xhale project (113 lungs in 2018, 104 lungs in 2019 and 88 lungs in 2020)
WP 2: "analysis of human lung explants - characterization of the inflammome in NNLDs"
This WP is now a standardized part of our routine workup of lung samples and allowed us great insights into the pathobiology of different NNLDs. We were able to set apart different NNLDs due to their underlying molecular characteristics and provide predictive algorithm that are able to identify a fibrotic pattern with a “90% certainty".
WP 3: From predicted pathomechanisms to certainty - analysis of precision-cut lung slices (PCLS) from explants
The tissue culture of human lung tissue has successfully been established in our lab as a reliable tool for the analysis of NNLD. We successfully cultured pulmonary specimens for 6 weeks and holistically anaöyzed more than 1.000 samples in detail regarding viability of different cell types, gene expression and histology.
The Challenge of Long-Term Cultivation of Human PCLS. Preuß EB et al. Am J Pathol. 2022 Feb;192(2):239-253. doi: 10.1016/j.ajpath.2021.10.020.
Nintedanib modulates collagen turnover in PCLS from fibrosis rats and patients with pulmonary fibrosis. Hesse C…. Respir Res. 2022 Aug 4;23(1):201. doi: 10.1186/s12931-022-02116-4.
Competitive fitness of Pseudomonas aeruginosa isolates in human and murine precision-cut lung slices. Cramer N,… Front Cell Infect Microbiol. 2022 Aug 23;12:992214. doi: 10.3389/fcimb.2022.992214.
WP 4: Molecular investigation of the angiogeneic driver of NNLD remodelling
We analyzed specific vascular changes specifically associated with different forms of fibrotic NNLD remodelling. Intussusceptive neoangiogenesis, which is not only a typical trait of AFE and NSIP, but also of COVID-19 lung pathology, turned out to be involved with the long term complications that SARS-CoV-2 survivors suffer from and it also presents a possible molecular access point for inhibitory therapy.
The most striking progress beyond the state of the art is our groundbreaking new imaging technique referred to as hierarchical Phase-Contrast Tomography (HiP-CT) at the European Synchrotron Radiation Facility in Grenoble. HiP-CT is an X-ray technique that allows whole organs to be imaged down to a resolution of 1 micron, or 100 times the resolution of a conventional CT scan. Thereby, the vascular and airway alterations in COVID-19 could be visualized and quantified, as never before. These studies were published in the top-tier journals Nature Methods and the American Journal of Respiratory and Critical Care Medicine, again to wide scientific acclaim. HiP-CT is filling a vast gap between clinical radiology and pathology which allows a correlation between high-resolution imaging, molecular radiomics and histology. The Chan Zuckerberg Initiative awarded us and our collaborators more than 8 million USD for this Deep Imaging Project after the end of XHaLe. The French government granted us privileged access to the facility and kept ESRF-EBS as the only beamline in Europe online to help fight the COVID-19 pandemic. HiP-CT has also enabled us to see how COVID-19 alters the structure of the blood vessel network in the whole lung, which was not possible so far at such a high resolution. The results of this warp speed project is awe-inspiring: an organ-wide view like a standard medical CT scan, but with one million times more information enabled for this first time by world’s brightest x-rays at ESRF.
All these efforts will provide much deeper insights in pulmonary diseases and be involved in therapeutic solutions.
All these efforts will provide much deeper insights in pulmonary diseases and be involved in therapeutic solutions.