Universität zu Köln

Haznedar Karakaya, Pinar ORCID: 0000-0002-2548-9979 (2023). The role of matrix metalloproteinase-12 (MMP-12) in hyperoxia-induced lung injury in a mouse model of bronchopulmonary dysplasia. PhD thesis, Universität zu Köln.

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Abstract

Premature infants who are exposed to prolonged oxygen (O2) therapy often develop Bronchopulmonary Dysplasia (BPD), a chronic inflammatory lung disease characterized by reduced alveolar formation and matrix remodelling. Matrix metalloproteinase-12 (MMP-12) is an important regulator of the extracellular matrix (ECM) and involved in the pathogenesis of lung diseases, e.g., chronic obstructive pulmonary disease (COPD) and emphysema. Since MMP-12 regulates elastic fibers, inflammation, and angiogenesis, we hypothesized that MMP-12 deficiency enables alveolar growth in hyperoxia-induced neonatal lung injury as a model of BPD. Specifically, we investigated the role of MMP-12 in (1) alveolar structure and pulmonary angiogenesis, (2) extracellular matrix metabolism as well as (3) macrophage activation. To address these research questions, newborn wildtype mice (WT) and MMP-12 deficient mice (MMP12-/-) were exposed to either hyperoxia (85% O2) or normoxia (21% O2) from postnatal day 1 (P1) to P14. Starting at P15 all animals were exposed to 21% O2 for recovery. At P28, lungs were excised en bloc and the tissue samples were either snap-frozen in liquid nitrogen or pressure-fixed in paraformaldehyde for molecular and biochemical investigations as well as quantitative histomorphometry and immunostainings. (1) Quantitative histomorphometric analyses revealed that lungs of WT animals had reduced alveolar and microvascular formation after hyperoxia; however, these pathological changes were significantly attenuated in MMP12-/- mice when compared to WT. (2) The assessment of elastic fibers and collagen showed that the distorted elastic fibers and the increase of collagen observed in WT animals after hyperoxia and indictive for fibrotic processes, were mitigated in lungs of MMP12-/- mice. In addition to these morphological improvements, the loss of MMP-12 promoted the gene expressions of surfactant proteins (Stfpb, Stfpc) and prevented the activation of TGF-β signalling under hyperoxia. (3) Finally, MMP12-/- mice were protected from macrophage influx after hyperoxia. In summary, the present study demonstrates that loss of MMP-12 enables alveolar and microvsascular formation, attenuates matrix remodelling and mitigates inflammation in neonatal lungs after hyperoxia, offering a possible new therapeutic target to treat BPD.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Haznedar Karakaya, Pinar haznedarp@gmail.com orcid.org/0000-0002-2548-9979 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-656210
Date:	2023
Language:	English
Faculty:	Faculty of Medicine
Divisions:	Faculty of Medicine > Experimentelle Medizin
Subjects:	Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language Matrix metalloproteinase-12 English Newborn English Bronchopulmonary dysplasia English
Date of oral exam:	8 March 2023
Referee:	Name Academic Title Alejandre Alcázar, Miguel Angel Dr. med. Dr. nat. med. Moinzadeh, Pia Dr. med
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/65621