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Mesenchymal stem cell-mediated reversal of bronchopulmonary dysplasia and associated pulmonary hypertension.

ABSTRACT: Clinical trials have failed to demonstrate an effective preventative or therapeutic strategy for bronchopulmonary dysplasia (BPD), a multifactorial chronic lung disease in preterm infants frequently complicated by pulmonary hypertension (PH). Mesenchymal stem cells (MSCs) and their secreted components have been shown to prevent BPD and pulmonary fibrosis in rodent models. We hypothesized that treatment with conditioned media (CM) from cultured mouse bone marrow-derived MSCs could reverse hyperoxia-induced BPD and PH. Newborn mice were exposed to hyperoxia (FiO(2)=0.75) for two weeks, were then treated with one intravenous dose of CM from either MSCs or primary mouse lung fibroblasts (MLFs), and placed in room air for two to four weeks. Histological analysis of lungs harvested at four weeks of age was performed to determine the degree of alveolar injury, blood vessel number, and vascular remodeling. At age six weeks, pulmonary artery pressure (PA acceleration time) and right ventricular hypertrophy (RVH; RV wall thickness) were assessed by echocardiography, and pulmonary function tests were conducted. When compared to MLF-CM, a single dose of MSC-CM-treatment (1) reversed the hyperoxia-induced parenchymal fibrosis and peripheral PA devascularization (pruning), (2) partially reversed alveolar injury, (3) normalized lung function (airway resistance, dynamic lung compliance), (4) fully reversed the moderate PH and RVH, and (5) attenuated peripheral PA muscularization associated with hyperoxia-induced BPD. Reversal of key features of hyperoxia-induced BPD and its long-term adverse effects on lung function can be achieved by a single intravenous dose of MSC-CM, thereby pointing toward a new therapeutic intervention for chronic lung diseases.

SUBMITTER: Hansmann G

PROVIDER: S-EPMC3401871 | biostudies-literature | 2012 Apr-Jun

REPOSITORIES: biostudies-literature

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Mesenchymal stem cell-mediated reversal of bronchopulmonary dysplasia and associated pulmonary hypertension.

Hansmann Georg G Fernandez-Gonzalez Angeles A Aslam Muhammad M Vitali Sally H SH Martin Thomas T Mitsialis S Alex SA Kourembanas Stella S

Pulmonary circulation 20120401 2

Clinical trials have failed to demonstrate an effective preventative or therapeutic strategy for bronchopulmonary dysplasia (BPD), a multifactorial chronic lung disease in preterm infants frequently complicated by pulmonary hypertension (PH). Mesenchymal stem cells (MSCs) and their secreted components have been shown to prevent BPD and pulmonary fibrosis in rodent models. We hypothesized that treatment with conditioned media (CM) from cultured mouse bone marrow-derived MSCs could reverse hyperox ...[more]

PMID: 22837858

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Project description:Bronchopulmonary dysplasia (BPD) is a major complication in prematurely born infants. Pulmonary hypertension (PH) associated with BPD (BPD-PH) is characterized by alveolar diffusion impairment, abnormal vascular remodeling, and rarefication of pulmonary vessels (vascular growth arrest), which lead to increased pulmonary vascular resistance and right heart failure. About 25% of infants with moderate to severe BPD develop BPD-PH that is associated with high morbidity and mortality. The recent evolution of broader PH-targeted pharmacotherapy in adults has opened up new treatment options for infants with BPD-PH. Sildenafil became the mainstay of contemporary BPD-PH therapy. Additional medications, such as endothelin receptor antagonists and prostacyclin analogs/mimetics, are increasingly being investigated in infants with PH. However, pediatric data from prospective or randomized controlled trials are still sparse. We discuss comprehensive diagnostic and therapeutic strategies for BPD-PH and briefly review the relevant differential diagnoses of parenchymal and interstitial developmental lung diseases. In addition, we provide a practical framework for the management of children with BPD-PH, incorporating the modified definition and classification of pediatric PH from the 2018 World Symposium on Pulmonary Hypertension, and the 2019 EPPVDN consensus recommendations on established and newly developed therapeutic strategies. Finally, current gaps of knowledge and future research directions are discussed. IMPACT: PH in BPD substantially increases mortality. Treatment of BPD-PH should be conducted by an interdisciplinary team and follow our new treatment algorithm while still kept tailored to the individual patient. We discuss recent developments in BPD-PH, make recommendations on diagnosis, monitoring and treatment of PH in BPD, and address current gaps of knowledge and potential research directions. We provide a practical framework, including a new treatment algorithm, for the management of children with BPD-PH, incorporating the modified definition and classification of pediatric PH (2018 WSPH) and the 2019 EPPVDN consensus recommendations on established and newly developed therapeutic strategies for BPD-PH.

Project description:BackgroundBronchopulmonary dysplasia (BPD) associated with pulmonary hypertension (PH) is a significant source of morbidity and mortality in premature infants. Recent advances have allowed the use of cardiovascular magnetic resonance (CMR) in the assessment of respiratory and cardiac disease in infants with BPD. In adults and older pediatric patients, decreased CMR interventricular septal curvature correlates with increased mean pulmonary artery pressure and pulmonary vascular resistance. The current study sought to determine the relationship of CMR derived septal curvature in neonates with BPD and BPD-PH with a need for PH therapy.MethodsForty moderate or severe BPD and 12 mild BPD or control infants were imaged without contrast between 38 and 47 weeks post-menstrual age on a neonatal-sized, neonatal intensive care unit-sited 1.5 T CMR scanner. CMR indices including eccentricity index (CMR-EI) and septal curvature were measured and compared to BPD severity and clinical outcomes including hospital length of stay (LOS), duration of respiratory support, respiratory support level at discharge and PH therapy.ResultsCMR-EI was directly associated and septal curvature was inversely associated with BPD severity. In a univariate analysis, CMR-EI and septal curvature were associated with increased hospital LOS, duration of respiratory support, respiratory support at hospital discharge, and need for PH therapy. In multivariable analysis CMR-EI was associated with hospital LOS and duration of respiratory support and septal curvature was associated with respiratory support at hospital discharge. Septal curvature was the only clinical or CMR variable associated with need for PH therapy (R2 = 0.66, p = 0.0014) in multivariable analysis demonstrating improved discrimination beyond CMR-EI.ConclusionsCMR derived septal curvature correlates significantly with clinical outcomes including hospital LOS, duration of respiratory support, respiratory support level at hospital discharge, and PH therapy in neonates with BPD and BPD-PH. Further, CMR derived septal curvature demonstrated improved discrimination of need for PH therapy and respiratory support at discharge compared to clinical variables and other CMR indices, supporting septal curvature as a non-invasive marker of PH in this population with potential to guide management strategies.

Dataset Information

Mesenchymal stem cell-mediated reversal of bronchopulmonary dysplasia and associated pulmonary hypertension.

Publications

Mesenchymal stem cell-mediated reversal of bronchopulmonary dysplasia and associated pulmonary hypertension.

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