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Experimental Lung Models

Dr. Ingrid Hennecke

From 1997 to 2004 Ingrid Henneke studied veterinary medicine at the Justus-Liebig University in Giessen. Subsequently, she did her doctorate at the Justus-Liebig University on the subject of "Influence of urokinase inhibitors on primary tumor growth and metastasis of small-cell and non-small-cell lung cancer".

After completing her doctorate, she was in charge of the animal experiments of the research group in which she was doing her doctorate. During this time, Dr. Henneke was mainly working on experimental models of lung fibrosis. Since 2015, her field of activity has primarily included providing animal research advice to the scientists of the working groups in planning, applying for and carrying out their animal experiments, writing applications for animal experiments and coordinating the breeding of genetically modified mouse lines.

Since 2015 Dr. Henneke has been training to become a specialist veterinarian for laboratory animal science. Since the beginning of 2018 she is supervising the practical part of the laboratory animal science courses, which are held at the Justus-Liebig University.

During the past several years Dr. Henneke was gaining experience in different experimental rodent models for lung diseases (lung cancer, lung fibrosis, pulmonary hypertension and COPD).

Lung Cancer

Xenograft/orthrotropic model: In this model mouse and human tumor xenografts are implanted in immune-deficient mice (athymic nude mice, SCID mice and NSG mice) or wild type (C57BL6) mouse. Orthotropic/xenograft models using several human and mouse lung cell lines. For primary tumor cells are instilled intratracheally into mice. For the development of lung tumor metastasis, i) tumor cells are injected via tail vein (i.v), and ii) primary tumors are surgically removed and mice are left to develop lung metastasis.

Genetically engineered animals: Genetically engineered mouse models of cancer provide invaluable tools to study the oncogenic process in lung cancer. We are using transgenic lung tumor models employing oncogenes such as KRas LA2 and KRas GD12 (collaboration with Prof. Tyler Jacks), cRaf and bRaf (collaboration with Prof. Ulf Rapp).

Urethane induced lung adenocarcinoma model: Chemically induced lung cancer has a rich history and valuable role in experimental oncology. We are using urethane induced lung tumor model (collaboration with Georgios T Stathopoulos). Urethane typically induces bronchioalveolar adenomas and, to a lesser extent, adenocarcinomas that resemble the adenocarcinoma subtype of non–small cell lung carcinoma.

Lung Fibrosis

Bleomycin model: The bleomycin induced model of pulmonary fibrosis is well established in our institute. It is by far the most widespread and best characterized model of pulmonary fibrosis and is therefore still the standard model for lung fibrosis.

Amiodarone model: Amiodarone is an iodinated benzofuran derivative, especially known for its antiarrhythmic properties. However, it excerts serious side effects in patients. Amiodarone is well-known to induce apoptosis of type II alveolar epithelial cells, a mechanism that has been suggested to play an important role in lung fibrosis.

Pulmonary Hypertension (PH)

Hypoxia model: Chronic hypoxia induced PH is intended to emulate class 3 of the WHO assessment (PH in the case of lung diseases and / or hypoxia). Exposure to chronic hypoxia leads to a mild form of PH and is characterized by a thickening of the vascular media with increased smooth muscle cells.

Hypoxia+ Sugen-5416 model: The induction of PH by VEGF receptor blocker in addition to chronic hypoxia reflects PH of group 1 (pulmonary arterial hypertension (PAH)).

Monocrotaline model: This model produces PH with a strongly inflammatory component in the rat. The monocrotaline model depicts vascular changes in the lungs as well as RVH as central features of the human disease and is recognized as a model of PH class 1 (PAH).

Partial occlusion of the pulmonary vein model: PH group 2 probably represents the largest proportion of patients with clinically relevant PH worldwide. However, compared to models that imitate PH group 1, for PH group 2 hardly any models have been able to establish themselves in the scientific community. In our institute, we are establishing a model of PH group 2 caused by partial occlusion of the pulmonary veins (pulmonary vein banding).

Chronic intermittent hypoxia model: Obstructive sleep apnea (OSA) is a risk factor for arterial hypertension. OSA is a serious human disease that is associated with changes in the cardiovascular system, including the development of arterial and pulmonary hypertension. The best described methodology for simulating OSA is that of chronic intermittent hypoxia (CIH). In this model, which is also established in our institute, the approach to generate the pathophysiological processes is not obstruction, but the resulting CIH, which is one of the most important factors in the pathogenesis of OSA and in the development of cardiovascular diseases.

Right Ventricular Hypertrophy

Pulmonary artery banding model: The model of pulmonary artery banding (PAB) induces right ventricular hypertrophy, but no PH. This model enables to investigate the pathomechanisms of right heart hypertrophy triggered by PH independently of changes in the pulmonary vessels. Therefore, this model is suitable for investigating special therapeutic approaches for the treatment of right heart hypertrophy.

Lung Emphysema/COPD

Smoke model: The model of smoke induced COPD has been established in our laboratory for a long time. After three months of smoke exposure, vascular changes in form of vascular remodeling processes and an increase in right ventricular systolic pressure (RVSP) can be demonstrated. After 8 months, emphysematous changes are evident. In addition, right heart hypertrophy becomes apparent after 8 months. The smoke model thus depicts vascular and alveolar changes, which can also be found in COPD patients.

Elastase model: Another model of lung emphysema, used in our institute, is the elastase model. Pulmonary emphysema is a typical feature of COPD. The elastase model reflects in particular a group of COPD patients who have a congenital alpha 1-antitrypsin deficiency, as a result of which the lungs are degraded by an excess of proteases. This model of emphysema achieved by intratracheal elastase application has been established and recognized in scientific research for a long time.

Publications Lung Cancer

Henneke I, Greschus S, Savai R, Korfei M, Markart P, Mahavadi P, Schermuly RT, Wygrecka M, Stürzebecher J, Seeger W, Günther A, Ruppert C. Inhibition of urokinase activity reduces primary tumor growth and metastasis formation in a murine lung carcinoma model. Am J Respir Crit Care Med. 2010 Mar 15;181(6):611-9. (selected as cover page)

Sarode P, Zheng X, Giotopoulou G, Weigert A, Kuenne C, Gunther S, Tretyn A, Gattenlöhner S, Stiewe T, Grimminger F, Georgios T. Stathopoulos2, Pullamsetti SS, Seeger W, Savai R. Tumor-associated macrophage-specific ß-catenin-FOSL2-ARID5A signaling is a major driver of macrophage programming and progression of lung cancer. Sci Adv, 05 Jun 2020:vol. 6, no. 23, eaaz6105

El-Nikhely N, Karger A, Sarode P, Singh I, Weigert A, Wietelmann A, Stiewe T, Dammann R, Fink L, Grimminger F, Barreto G, Seeger W, Pullamsetti SS, Rapp UR, Savai R. Metastasis-Associated Protein 2 Represses NF-κB to Reduce Lung Tumor Growth and Inflammation. Cancer Res. 2020 Oct 1;80(19):4199-4211.

Salazar Y, Zheng X, Brunn D, Raifer H, Vogel D, Winter H, Guenther S, Weigert A, Schmall A, Tufman A, Fink L, Brüne B, Grimminger F, Seeger W, Pullamsetti SS, Huber M, Savai R. Microenvironmental Th9– and Th17– lymphocytes induce metastatic spreading in lung cancer. J Clin Invest. 2020 Jun 2:124037.

Pullamsetti SS, Kojonazarov B, Storn S, Gall H, Salazar Y, Wolf J, Weigert A, El-Nikhely N, Ghofrani HA, Krombach GA, Fink L, Gattenlöhner S, Rapp UR, Schermuly RT, Grimminger F, Seeger W, Savai R. Lung cancer–associated pulmonary hypertension: role of microenvironmental inflammation based on tumor cell-immune cell crosstalk. Sci Transl Med. 2017; 15;9(416)

Schmall A, Al-Tamari HM, Herold S, Kampschulte M, Weigert A, Wietelmann A, Vipotnik N, Grimminger F, Seeger W, Pullamsetti SS, Savai R. Macrophage and Cancer Cell Crosstalk via CCR2 and CX3CR1 is a Fundamental Mechanism Driving Lung Cancer. Am J Respir Crit Care Med. 2015;191(4):437-47.

Savai R, Schermuly RT, Pullamsetti SS, Schneider M, Greschus S, Ghofrani HA, Traupe H, Grimminger F, Banat GA. A Combination of hybrid-based vaccination and cellular therapy prevent tumor growth by enforcing FAS/FASL-mediated cytotoxicity. Cancer Res. 2007;67(11):5443-53.

Publications Lung Fibrosis

Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis.

Korfei M, Ruppert C, Mahavadi P, Henneke I, Markart P, Koch M, Lang G, Fink L, Bohle RM, Seeger W, Weaver TE, Guenther A. Am J Respir Crit Care Med. 2008 Oct 15;178(8):838-46. doi: 10.1164/rccm.200802-313OC. Epub 2008 Jul 17. PMID: 18635891

Role of protease-activated receptor-2 in idiopathic pulmonary fibrosis.

Wygrecka M, Kwapiszewska G, Jablonska E, von Gerlach S, Henneke I, Zakrzewicz D, Guenther A, Preissner KT, Markart P. Am J Respir Crit Care Med. 2011 Jun 15;183(12):1703-14. doi: 10.1164/rccm.201009-1479OC. Epub 2011 Mar 11. PMID: 21471103

Attenuating endogenous Fgfr2b ligands during bleomycin-induced lung fibrosis does not compromise murine lung repair.

MacKenzie B, Henneke I, Hezel S, Al Alam D, El Agha E, Chao CM, Quantius J, Wilhelm J, Jones M, Goth K, Li X, Seeger W, Königshoff M, Herold S, Rizvanov AA, Günther A, Bellusci S. Am J Physiol Lung Cell Mol Physiol. 2015 May 15;308(10):L1014-24. doi: 10.1152/ajplung.00291.2014. Epub 2015 Mar 27. PMID: 25820524

Two-Way Conversion between Lipogenic and Myogenic Fibroblastic Phenotypes Marks the Progression and Resolution of Lung Fibrosis.

El Agha E, Moiseenko A, Kheirollahi V, De Langhe S, Crnkovic S, Kwapiszewska G, Szibor M, Kosanovic D, Schwind F, Schermuly RT, Henneke I, MacKenzie B, Quantius J, Herold S, Ntokou A, Ahlbrecht K, Braun T, Morty RE, Günther A, Seeger W, Bellusci S. Cell Stem Cell. 2017 Apr 6;20(4):571. doi: 10.1016/j.stem.2017.03.011. PMID: 28388434

Altered surfactant homeostasis and alveolar epithelial cell stress in amiodarone-induced lung fibrosis.

Mahavadi P, Henneke I, Ruppert C, Knudsen L, Venkatesan S, Liebisch G, Chambers RC, Ochs M, Schmitz G, Vancheri C, Seeger W, Korfei M, Guenther A. Toxicol Sci. 2014 Nov;142(1):285-97. doi: 10.1093/toxsci/kfu177. Epub 2014 Aug 27. PMID: 25163675

Regulation of macroautophagy in amiodarone-induced pulmonary fibrosis.

Mahavadi P, Knudsen L, Venkatesan S, Henneke I, Hegermann J, Wrede C, Ochs M, Ahuja S, Chillappagari S, Ruppert C, Seeger W, Korfei M, Guenther A. J Pathol Clin Res. 2015 Jun 3;1(4):252-63. doi: 10.1002/cjp2.20. eCollection 2015 Oct. PMID: 27499909

Pullamsetti SS, Savai R, Dumitrascu R, Dahal BK, Wilhelm J, Konigshoff M, Zakrzewicz D, Ghofrani HA, Weissmann N, Eickelberg O, Guenther A, Leiper J, Seeger W, Grimminger F, Schermuly RT. The role of dimethylarginine dimethylaminohydrolase in idiopathic pulmonary fibrosis. Sci Transl Med. 2011;3(87):87ra53.

Al-Tamari HM, Dabral S, Schmall A, Sarvari P, Ruppert C, Paik J, DePinho RA, Grimminger F, Eickelberg O, Guenther A, Seeger W, Savai R, Pullamsetti SS. FoxO3 an important player in fibrogenesis and therapeutic target for idiopathic pulmonary fibrosis. EMBO Mol Med. 2018:276-293.

Publications COPD

NADPH oxidase subunit NOXO1 is a target for emphysema treatment in COPD.

Seimetz M, Sommer N, Bednorz M, Pak O, Veith C, Hadzic S, Gredic M, Parajuli N, Kojonazarov B, Kraut S, Wilhelm J, Knoepp F, Henneke I, Pichl A, Kanbagli ZI, Scheibe S, Fysikopoulos A, Wu CY, Klepetko W, Jaksch P, Eichstaedt C, Grünig E, Hinderhofer K, Geiszt M, Müller N, Rezende F, Buchmann G, Wittig I, Hecker M, Hecker A, Padberg W, Dorfmüller P, Gattenlöhner S, Vogelmeier CF, Günther A, Karnati S, Baumgart-Vogt E, Schermuly RT, Ghofrani HA, Seeger W, Schröder K, Grimminger F, Brandes RP, Weissmann N. Nat Metab. 2020 Jun;2(6):532-546. doi: 10.1038/s42255-020-0215-8. Epub 2020 Jun 8. PMID: 32694733

Amelioration of elastase-induced lung emphysema and reversal of pulmonary hypertension by pharmacological iNOS inhibition in mice.

Fysikopoulos A, Seimetz M, Hadzic S, Knoepp F, Wu CY, Malkmus K, Wilhelm J, Pichl A, Bednorz M, Tadele Roxlau E, Ghofrani HA, Sommer N, Gierhardt M, Schermuly RT, Seeger W, Grimminger F, Weissmann N, Kraut S. Br J Pharmacol. 2021 Jan;178(1):152-171. doi: 10.1111/bph.15057. Epub 2020 Apr 28. PMID: 32201936 Formularbeginn

Inducible NOS inhibition reverses tobacco-smoke-induced emphysema and pulmonary hypertension in mice.

Seimetz M, Parajuli N, Pichl A, Veit F, Kwapiszewska G, Weisel FC, Milger K, Egemnazarov B, Turowska A, Fuchs B, Nikam S, Roth M, Sydykov A, Medebach T, Klepetko W, Jaksch P, Dumitrascu R, Garn H, Voswinckel R, Kostin S, Seeger W, Schermuly RT, Grimminger F, Ghofrani HA, Weissmann N. Cell. 2011 Oct 14;147(2):293-305. doi: 10.1016/j.cell.2011.08.035. PMID: 22000010

Publications Pulmonary Hypertension

Savai R, Al-Tamari HM, Sedding D, Kojonazarov B, Muecke C, Teske R, Capecchi MR, Weissmann N, Grimminger G, Seeger W, Schermuly RT, Pullamsetti SS. Pro-proliferative and inflammatory signaling converge on the FoxO1 transcription factor in pulmonary hypertension. Nat Med. 2014;20(11):1289-300.

Pullamsetti SS, Savai R, Schaefer MB, Wilhelm J, Ghofrani HA, Weissmann N, Schudt C, Fleming I, Mayer K, Leiper J, Seeger W, Grimminger F, Schermuly RT. cAMP phosphodiesterase inhibitors increases nitric oxide production by modulating dimethylarginine dimethylaminohydrolases. Circulation. 2011;123(11):1194-204.

Dabral S, Muecke C, Valasarajan C, Schmoranzer M, Wietelmann A, Semenza GL, Meister M, Muley T, Seeger-Nukpezah T, Samakovlis C, Weissmann N, Grimminger F, Seeger W, Savai R, Pullamsetti SS. A RASSF1A-HIF1α loop drives Warburg effect in cancer and pulmonary hypertension. Nat Commun. 2019;10(1):2130.

Evidence for the Fucoidan/P-Selectin Axis as a Therapeutic Target in Hypoxia-induced Pulmonary Hypertension.

Novoyatleva T, Kojonazarov B, Owczarek A, Veeroju S, Rai N, Henneke I, Böhm M, Grimminger F, Ghofrani HA, Seeger W, Weissmann N, Schermuly RT. Am J Respir Crit Care Med. 2019 Jun 1;199(11):1407-1420. doi: 10.1164/rccm.201806-1170OC. PMID: 30557519

Targeting cyclin-dependent kinases for the treatment of pulmonary arterial hypertension.

Weiss A, Neubauer MC, Yerabolu D, Kojonazarov B, Schlueter BC, Neubert L, Jonigk D, Baal N, Ruppert C, Dorfmuller P, Pullamsetti SS, Weissmann N, Ghofrani HA, Grimminger F, Seeger W, Schermuly RT. Nat Commun. 2019 May 17;10(1):2204. doi: 10.1038/s41467-019-10135-x. PMID: 31101827

p38 MAPK Inhibition Improves Heart Function in Pressure-Loaded Right Ventricular Hypertrophy.

Kojonazarov B, Novoyatleva T, Boehm M, Happe C, Sibinska Z, Tian X, Sajjad A, Luitel H, Kriechling P, Posern G, Evans SM, Grimminger F, Ghofrani HA, Weissmann N, Bogaard HJ, Seeger W, Schermuly RT. Am J Respir Cell Mol Biol. 2017 Nov;57(5):603-614. doi: 10.1165/rcmb.2016-0374OC. PMID: 28657795

 

 

 

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