Universität zu Köln

Alcazar, Miguel A. Alejandre, Kaschwich, Mark, Ertsey, Robert, Preuss, Stefanie, Milla, Carlos, Mujahid, Sana, Masumi, Juliet, Khan, Suleman, Mokres, Lucia M., Tian, Lu, Mohr, Jasmine, Hirani, Dharmesh, V, Rabinovitch, Marlene and Bland, Richard D. (2018). Elafin Treatment Rescues EGFR-Klf4 Signaling and Lung Cell Survival in Ventilated Newborn Mice. Am. J. Respir. Cell Mol. Biol., 59 (5). S. 623 - 635. NEW YORK: AMER THORACIC SOC. ISSN 1535-4989

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Abstract

Mechanical ventilation with O-2-rich gas (MV-O-2) inhibits alveologenesis and lung growth. We previously showed that MV-O-2 increased elastase activity and apoptosis in lungs of newborn mice, whereas elastase inhibition by elafin suppressed apoptosis and enabled lung growth. Pilot studies suggested that MV-O-2 reduces lung expression of prosurvival factors phosphorylated epidermal growth factor receptor (pEGFR) and Kruppel-like factor 4 (Klf4). Here, we sought to determine whether apoptosis and lung growth arrest evoked by MV-O-2 reflect disrupted pEGFR-Klf4 signaling, which elafin treatment preserves, and to assess potential biomarkers of bronchopulmonary dysplasia (BPD). Five-day-old mice underwent MV with air or 40% O-2 for 8-24 hours with or without elafin treatment. Unventilated pups served as controls. Immunoblots were used to assess lung pEGFR and Klf4 proteins. Cultured MLE-12 cells were exposed to AG1478 (EGFR inhibitor), Klf4 siRNA, or vehicle to assess effects on proliferation, apoptosis, and EGFR regulation of Klf4. Plasma elastase and elafin levels were measured in extremely premature infants. In newborn mice, MV with air or 40% O-2 inhibited EGFR phosphorylation and suppressed Klf4 protein content in lungs (vs. unventilated controls), yielding increased apoptosis. Elafin treatment inhibited elastase, preserved lung pEGFR and Klf4, and attenuated the apoptosis observed in lungs of vehicle-treated mice. In MLE-12 studies, pharmacological inhibition of EGFR and siRNA suppression of Klf4 increased apoptosis and reduced proliferation, and EGFR inhibition decreased Klf4. Plasma elastase levels were more than twofold higher, without a compensating increase of plasma elafin, in infants with BPD, compared to infants without BPD. These findings indicate that pEGFR-Klf4 is a novel prosurvival signaling pathway in lung epithelium that MV disrupts. Elafin preserves pEGFR-Klf4 signaling and inhibits apoptosis, thereby enabling lung growth during MV. Together, our animal and human data raise the question: would elastase inhibition prevent BPD in high-risk infants exposed to MV-O-2?

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Alcazar, Miguel A. Alejandre UNSPECIFIED UNSPECIFIED UNSPECIFIED Kaschwich, Mark UNSPECIFIED UNSPECIFIED UNSPECIFIED Ertsey, Robert UNSPECIFIED UNSPECIFIED UNSPECIFIED Preuss, Stefanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Milla, Carlos UNSPECIFIED UNSPECIFIED UNSPECIFIED Mujahid, Sana UNSPECIFIED UNSPECIFIED UNSPECIFIED Masumi, Juliet UNSPECIFIED UNSPECIFIED UNSPECIFIED Khan, Suleman UNSPECIFIED UNSPECIFIED UNSPECIFIED Mokres, Lucia M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tian, Lu UNSPECIFIED UNSPECIFIED UNSPECIFIED Mohr, Jasmine UNSPECIFIED UNSPECIFIED UNSPECIFIED Hirani, Dharmesh, V UNSPECIFIED UNSPECIFIED UNSPECIFIED Rabinovitch, Marlene UNSPECIFIED UNSPECIFIED UNSPECIFIED Bland, Richard D. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-168010
DOI:	10.1165/rcmb.2017-0332OC
Journal or Publication Title:	Am. J. Respir. Cell Mol. Biol.
Volume:	59
Number:	5
Page Range:	S. 623 - 635
Date:	2018
Publisher:	AMER THORACIC SOC
Place of Publication:	NEW YORK
ISSN:	1535-4989
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EPIDERMAL-GROWTH-FACTOR; PROTEINASE-INHIBITOR IMBALANCE; BRONCHOPULMONARY DYSPLASIA; MECHANICAL VENTILATION; ALVEOLAR SEPTATION; FACTOR RECEPTOR; PRETERM LAMBS; PULMONARY-HYPERTENSION; GENE-EXPRESSION; NEONATAL MICE Multiple languages Biochemistry & Molecular Biology; Cell Biology; Respiratory System Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/16801