Person:

Leeman, Kristen

Bronchopulmonary dysplasia (BPD) is a major complication of preterm birth and has serious adverse long-term health consequences. The etiology of BPD is complex, multifactorial, and incompletely understood. Contributing factors include ventilator-induced lung injury, exposure to toxic oxygen levels, and infection. Several preventive and therapeutic strategies have been developed with variable success. These include lung protective ventilator strategies and pharmacological and nutritional interventions. These strategies target different components and stages of the disease process and they are commonly used in combination. The purpose of this review is to discuss the evidence for current pharmacological interventions and identify future therapeutic modalities that appear promising in the prevention and management of BPD. Continued improved understanding of BPD pathogenesis leads to opportunities for newer preventive approaches. These will need to be evaluated in the setting of current clinical practice in order to assess their efficacy.

Background: Integration of web-based educational tools into medical training has been shown to increase accessibility of resources and optimize teaching. We developed a web-based educational portal (WBEP) to support teaching of pediatric residents about newborn medicine by neonatology fellows. Objectives: 1) To compare residents’ attitudes about their fellow-led education in the NICU pre- and post-WBEP; including assessment of factors that impact their education and usefulness of teaching tools. 2) To compare fellow utilization of various teaching modalities pre- and post-WBEP. Design/methods We queried residents about their attitudes regarding fellow-led education efforts and various teaching modalities in the NICU and logistics potentially impacting effectiveness. Based on these data, we introduced the WBEP – a repository of teaching tools (e.g., mock code cases, board review questions, journal articles, case-based discussion scenarios) for use by fellows to supplement didactic sessions in a faculty-based curriculum. We surveyed residents about the effectiveness of fellow teaching pre- and post-WBEP implementation and the type of fellow-led teaching modalities that were used. Results: After analysis of survey responses, we identified that residents cited fellow level of interest as the most important factor impacting their education. Post-implementation, residents described greater utilization of various teaching modalities by fellows, including an increase in use of mock codes (14% to 76%, p<0.0001) and journal articles (33% to 59%, p=0.02). Conclusions: A web-based resource that supplements traditional curricula led to greater utilization of various teaching modalities by fellows and may encourage fellow involvement in resident teaching.

Obliterative bronchiolitis (OB) remains the most significant cause of death in long-term survival of lung transplantation. Using an established murine heterotopic tracheal allograft model, the effects of different routes of administration of bone marrow-derived multipotent stromal cells (MSCs) on the development of OB were evaluated. Tracheas from BALB/c mice were implanted into the subcutaneous tissue of major histocompatibility complex- (MHC-) disparate C57BL/6 mice. At the time of transplant, bone marrow-derived MSCs were administered either systemically or locally or via a combination of the two routes. The allografts were explanted at various time points after transplantation and were evaluated for epithelial integrity, inflammatory cell infiltration, fibrosis, and luminal obliteration. We found that the most effective route of bone marrow-derived MSC administration is the combination of systemic and local delivery. Treatment of recipient mice with MSCs suppressed neutrophil, macrophage, and T-cell infiltration and reduced fibrosis. These beneficial effects were observed despite lack of significant MSC epithelial engraftment or new epithelial cell generation. Our study suggests that optimal combination of systemic and local delivery of MSCs may ameliorate the development of obliterative airway disease through modulation of immune response.

Background: Despite advances in neonatal care, bronchopulmonary dysplasia (BPD) remains a significant contributor to infant mortality and morbidity. While human amnion epithelial cells (hAECs) have shown promise in small and large animal models of BPD, there is scarce information on long-term benefit and clinically relevant questions surrounding administration strategy remain unanswered. In assessing the therapeutic potential of hAECs, we investigated the impact of cell dosage, administration routes and timing of treatment in a pre-clinical model of BPD. Methods: Lipopolysaccharide was introduced intra-amniotically at day 16 of pregnancy prior to exposure to 65% oxygen (hyperoxia) at birth. hAECs were administered either 12 hours (early) or 4 days (late) after hyperoxia commenced. Collective lung tissues were subjected to histological analysis, multikine ELISA for inflammatory cytokines, FACS for immune cell populations and 3D lung stem cell culture at neonatal stage (postnatal day 7 and 14). Invasive lung function test and echocardiography were applied at 6 and 10 weeks of age. Results: hAECs improved the tissue-to-airspace ratio and septal crest density in a dose-dependent manner, regardless of administration route. Early administration of hAECs, coinciding with the commencement of postnatal hyperoxia, was associated with reduced macrophages, dendritic cells and natural killer cells. This was not the case if hAECs were administered when lung injury was established. Fittingly, early hAEC treatment was more efficacious in reducing interleukin-1β, tumour necrosis factor alpha and monocyte chemoattractant protein-1 levels. Early hAEC treatment was also associated with reduced airway hyper-responsiveness and normalisation of pressure–volume loops. Pulmonary hypertension and right ventricle hypertrophy were also prevented in the early hAEC treatment group, and this persisted until 10 weeks of age. Conclusions: Early hAEC treatment appears to be advantageous over late treatment. There was no difference in efficacy between intravenous and intratracheal administration. The benefits of hAEC administration resulted in long-term improvements in cardiorespiratory function. Electronic supplementary material The online version of this article (doi:10.1186/s13287-017-0689-9) contains supplementary material, which is available to authorized users.

Rapid whole-exome sequencing (rWES) is used in critically ill newborn infants to inform about diagnosis, clinical management, and prognosis. Here we report a male newborn infant with hydrops, pancytopenia, and acute liver failure who was listed for liver transplantation. Given the acuity of the presentation, the procedure-related morbidity and mortality, and lack of diagnosis, we used rWES in the proband and both parents with a turnaround time of 10 business days. rWES returned one maternally inherited, likely pathogenic and one paternally inherited, likely pathogenic variant in NPC1, suggestive of a diagnosis of Niemann–Pick disease type C (NPC). Interestingly, a diagnosis of NPC was entertained prior to rWES, but deemed unlikely in light of absent cholesterol storage on liver biopsy and near-normal oxysterol levels in dried blood. The diagnosis of NPC was confirmed on filipin stain in fibroblasts demonstrating defective cholesterol trafficking. NPC is a slowly progressive neurodegenerative disorder that may also affect the liver with overall poor prognosis. It was decided to take the infant off the transplant list and transfer to palliative care, where he died after 4 wk. This case highlights the utility of rWES in an acute clinical setting for several domains of precision medicine including (1) diagnosis, (2) prognosis and outcome, (3) management and therapy, and (4) utilization of resources.

The mammalian lung is a complex organ containing numerous putative stem/progenitor cell populations that contribute to region-specific tissue homeostasis and repair. In this review, we discuss recent advances in identifying and studying these cell populations in the context of lung homeostasis and disease. Genetically engineered mice now allow for lineage tracing of several lung stem and progenitor cell populations in vivo during different types of lung injury repair. Using specific sets of cell surface markers, these cells can also be isolated from murine and human lung and tested in 3D culture systems and in vivo transplant assays. The pathology of devastating lung diseases, including lung cancers, is likely in part due to dysregulation and dysfunction of lung stem cells. More precise characterization of stem cells with identification of new, unique markers; improvement in isolation and transplant techniques; and further development of functional assays will ultimately lead to new therapies for a host of human lung diseases. In particular, lung cancer biology may be greatly informed by findings in normal lung stem cell biology as evidence suggests that lung cancer is a disease that begins in, and may be driven by, neoplastic lung stem cells.