Lung Diseases of the Newborn

Transcription

1 Lung Diseases of the Newborn PD Dr. med. Anne Hilgendorff Comprehensive Pneumology Center Perinatal Center LMU ispz Hauner Ludwig-Maximilians University und Helmholtz Zentrum München

2 Prematurity 1 % of all newborns are born < 32 weeks gestational age Significant improvement of survival rates due to advances in perinatal care Decreasing mortality leads to increased importance of long-term follow up Neurologic Development Metabolic and pulmonary Disorders

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5 Lung Function in Preterm Infants 6.0 * Sgaw SGaw (1/kPa*s -1 ) -1 ) FRC (ml/kg) before salbutamol inhalation after 0 before after salbutamol inhalation Hilgendorff et al, PCCM 200

6 Immature Lung Prenatal Infection Hypoxia Postnatal Infection Mechanical Ventilation 0 2 -Toxicity Genetic susceptibility Pulmonary Inflammation Altered Signal Transduction ECM Remodelling Reduced Alveolarization Impaired Vascularization Neonatal chronic lung disease

7 embryonic pseudoglandular canalicular saccular alveolar days p.c. age weeks p.c. age 5 d p.n. 36 weeks

8 Neonatal Chronic Lung Disease Chronic Lung Disease (BPD) in up to 35% of all preterms < 1500g Furmann et al. J Pediatr 1996 Rate of severe BPD decreasing, overall incidence unchanged(1994/2002) Smith, J. Pediatr 2005 Rehospitalisation during the 1st year of life Doyle et al. ADC 2001 Viral infections a.o. RSV is considerably increased - first data for H1N1 Clinical signs of airway obstruction (OR 2.7), medications with bronchodilators (OR 2.4 ) At school age, a persisiting high rate of respiratory symptoms (30-24%) in preterms with or without BPD Gross SJ et al. J Ped 1988

9 old BPD Fibrosis Atelectasis new BPD Alveolar hypoplasia Less fibrosis

10 From bench to bedside and back Biomarkers Lungs/body fluid neonatal mice Pathways Transgenic mice neonatal mice Structure Pulmonary µct Function Bodyplethysmography

11 Experimental Design : 21% / 40% O 180 bpm Control: Spontaneous breathing, 21% / 40% O 2 2 Hours 8 Hours 24 Hours - TV 5-9 µl/g bw - PIP cmh 2 O Tissue analysis: Histology, IHC, protein, RNA, functional assays, isolation of primary cells, in vivo andex vivo imaging

12 Thibeault DW, Pediatrics 111: , 2003.

13 ECM remodelling Prof. R. Bland Prof. M. Rabinovitch Stanford University Tropoelastin β-actin Tropoelastin Protein β-actin Protein 2 1 Eln +/+ Eln +/ * 67 kd 42 kd Desmosine [pm] Creatinine [mg] Eln +/+ Eln +/ * * Fibrillin-1 β-actin Fibrillin-1 Protein β-actin Protein 0.8 * 350 kd 42 kd 0 Control Control 0 Control Control 0 Eln +/+ Eln +/ Inflation Pressure [cmh 2 O] p < 0.01 Eln +/+ (n=5) Eln +/ (n=4) Inflation Pressure [cmh 2 O] Eln +/+ Eln +/ p > 0.05 (n=5) (n=4) Inflation Volume [µl/g bw] Inflation Volume [µl/g bw]

14 ECM remodelling Prof. R. Bland Prof. M. Rabinovitch Stanford University Unique preclinical model Investigation of transgenic mice Treatment options Mokres LM, Parai K, Hilgendorff A, et al. Am J Physiol Lung Cell Mol Physiol 2010 Hilgendorff A, et al. 2011; Am J Resp Crit Care Med 2011 Hilgendorff A, et al Am J Physiol Lung Cell Mol Physiol 2012

15 ECM remodelling R. Bland et al.

16 Pathogenesis Hilgendorff, A. et al. AJRCMB

17 Growth factors and lung diseases

18 Alveolarization & repair Cell Mouse Human Effect of stretch on mouse MFB PDGF-Rα signalling in neonatal lung injury in mice TGF-β effects on MFB (mouse & human) Proliferation murine MFB (un-stretched) PDGF-Rα +/+ PDGF-Rα +/- Stretch reduces VEGF-A production in mouse MFB Down-regulation of VEGF-A is PDGF-Rα related VEGF-A β-actin 42 kda 43 kda TGF-β response in un-stretched and stretched MFB match BPD disease grades 4 * Proliferation murine MFB (stretched) VEGF-A Protein/ β-actin Protein 2 0

19 Inflammatory changes in ncld BPD nobpd Ambalavanan et al, Pediatrics 2008 Jonsson et al, Arch Dis Child 1997

20 TNF-α and TGF-β signaling in experimental ncld Harald Ehrhardt Melina Kossert Active-Caspase-3 Protein/ β- Actin Protein Active-Caspase-6 Protein/ β -Actin Protein 20 * * TNF-α +/+ TNF-α -/ Monocytes / 100 Alveoli *** Control Control TNF-α +/+ TNF-α -/- 90 Rel. mrna MCP-1 0 Control 0 TNF-α +/+ TNF-α -/- Control TNF-α +/+ TNF-α -/- 0 psmad psmad Protein/ β- Actin Protein TNF-α +/+ TNF-α -/- β-actin * * TNF-α +/+ TNF-α -/- Mean & SD, n = 4-7/group, p < 0.05

21 Cell-specific delineation of underlying pathomechanisms Cell Mouse Human Early signatures following and hyperoxia mimicking ncld in mice Transcriptome pattern in the early diagnosis of ncld 5-7-day-old C57BL/6 mice (wild-type) (40% O2 for 8h) Controls (40% O2 for 8h) Hyperoxia (60% for 8h) Hyperoxia Controls (air (21%) for 8h) Anita Hoeland Total lung Cell isolation Total lung Cell isolation 102 up 134 down MFB ATII EC MFB ATII EC RNA-Microarray, Metbolomics, Proteomics

22 Increased monocyte signaling in BPD Discriminators: MCP-1 EGF Gestational Age (GA) Persistent Ductus Arteriosus (PDA) Congenital infection (CI) Luminex xmap of serum cord blood Orthogonal partial least squares discriminance analysis (OPLS-DA)

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24 Impaired vascular growth and function Infection Mechanical Ventilation Hyperoxia Inflammation Immature pulmonary vessels Structure Function Growth Hyperplasia of SMC Vasodilation Number of arteries Ingrowth of fibroblasts Hypoxic vasoconstriction Vascular surface area Thickening of adventia, collagen matrix Abnormal metabolic function Alveolarisation

25 BMP signaling in experimental ncld Sub-Activating Ligand, Normal BMPR2 Activating Ligand, Normal BMPR2 BMPR2 receptor BMP Type I receptor BMPR2 receptor BMP Type I receptor FKBP12 Calcineurin P FKBP12 Calcineurin No signaling Normal signaling Rapamycin - binding FKBP12 Cyclosporin - Calcineurin inhibitor FK506 -both

26 Book Chapter Understanding Lung Aging

27 Baraldi E, Filippone M. Chronic lung disease after premature birth. N Engl J Med. 2007;357(19):

28 Second Hit: Effects of modest intrauterine smoke exposure Ö. Yildirim, CPC Filter Air CS (500 mg/m 3-50 min/day), 40%O2 E 0 E 7 E PN 7 control FA CS

29 From bench to bedside and back Biomarkers Lungs/body fluid neonatal mice Biomarkers Urine, plasma and TA of preterms Proteomics HHZ Munich Pathways Preterm pulmonary MFB Pathways Transgenic mice neonatal mice AIRR preterm infants Structure Pulmonary MRI Structure Pulmonary µct Function Bodyplethysmography Function Bodyplethysmography Department of Radiology, Campus Grosshadern University Hospital Perinatal Center, Munich (LMU) and Giessen (UKGM) University Hospital, DZL

30 Cranial hemo-/hydrodynamics Resting state MRI T2 Mapping