Stromal derived factor-1 mediates the lung regenerative effects of mesenchymal stem cells in a rodent model of bronchopulmonary dysplasia.

BACKGROUND: Mesenchymal stem cells (MSCs) attenuate lung injury in experimental models of bronchopulmonary dysplasia (BPD). Stromal derived factor-1 (SDF-1), a chemokine secreted by MSCs, modulates angiogenesis and stem cell recruitment. Here we tested the hypothesis that SDF-1 mediates MSC protective effects in experimental BPD by modulating angiogenesis. METHODS: SDF-1 was knocked down in MSCs using lentiviral vectors carrying anti-SDF-1 short hairpin RNA (MSC-SDF KD). Non-silencing short hairpin RNA was used as control (MSC-NS control). Newborn rats exposed to normoxia or hyperoxia (FiO2 = 0.85) for 3 weeks, were randomly assigned to receive a single intra-tracheal injection (IT) of MSC-NS control or MSC-SDF KD (1 × 106 cells/50 µl) or placebo on postnatal day 7. The degree of alveolarization, lung angiogenesis, inflammation, and pulmonary hypertension (PH) were assessed at postnatal day 21. RESULTS: Administration of IT MSC-NS control improved lung alveolarization, angiogenesis and inflammation, and attenuated PH in newborn rats with hyperoxia-induced lung injury (HILI). In contrast, knockdown of SDF-1 in MSCs significantly reduced their beneficial effects on alveolarization, angiogenesis, inflammation and PH. CONCLUSIONS: The therapeutic benefits of MSCs in neonatal HILI are in part mediated by SDF-1, through anti-inflammatory and angiogenesis promoting mechanisms. Therapies directly targeting this chemokine may provide a novel strategy for the treatment of BPD.

CXCR4 blockade attenuates hyperoxia-induced lung injury in neonatal rats.

BACKGROUND: Lung inflammation is a key factor in the pathogenesis of bronchopulmonary dysplasia (BPD). Stromal-derived factor-1 (SDF-1) and its receptor chemokine receptor 4 (CXCR4) modulate the inflammatory response. It is not known if antagonism of CXCR4 alleviates lung inflammation in neonatal hyperoxia-induced lung injury. OBJECTIVE: We aimed to determine whether CXCR4 antagonism would attenuate lung injury in rodents with experimental BPD by decreasing pulmonary inflammation. METHODS: Newborn rats exposed to normoxia (room air, RA) or hyperoxia (FiO2 = 0.9) from postnatal day 2 (P2) to P16 were randomized to receive the CXCR4 antagonist, AMD3100 or placebo (PL) from P5 to P15. Lung alveolarization, angiogenesis and inflammation were evaluated at P16. RESULTS: Compared to the RA pups, hyperoxic PL pups had a decrease in alveolarization, reduced lung vascular density and increased lung inflammation. In contrast, AMD3100-treated hyperoxic pups had improved alveolarization and increased angiogenesis. This improvement in lung structure was accompanied by a decrease in the macrophage and neutrophil counts in the bronchoalveolar lavage fluid and reduced lung myeloperoxidase activity. CONCLUSION: CXCR4 antagonism decreases lung inflammation and improves alveolar and vascular structure in neonatal rats with experimental BPD. These findings suggest a novel therapeutic strategy to alleviate lung injury in preterm infants with BPD.

Bone marrow-derived c-kit+ cells attenuate neonatal hyperoxia-induced lung injury.

Recent studies suggest that bone marrow (BM)-derived stem cells have therapeutic efficacy in neonatal hyperoxia-induced lung injury (HILI). c-kit, a tyrosine kinase receptor that regulates angiogenesis, is expressed on several populations of BM-derived cells. Preterm infants exposed to hyperoxia have decreased lung angiogenesis. Here we tested the hypothesis that administration of BM-derived c-kit(+) cells would improve angiogenesis in neonatal rats with HILI. To determine whether intratracheal (IT) administration of BM-derived c-kit(+) cells attenuates neonatal HILI, rat pups exposed to either normobaric normoxia (21% O2) or hyperoxia (90% O2) from postnatal day (P) 2 to P15 were randomly assigned to receive either IT BM-derived green fluorescent protein (GFP)(+) c-kit(-) cells (PL) or BM-derived GFP(+) c-kit(+) cells on P8. The effect of cell therapy on lung angiogenesis, alveolarization, pulmonary hypertension, vascular remodeling, cell proliferation, and apoptosis was determined at P15. Cell engraftment was determined by GFP immunostaining. Compared to PL, the IT administration of BM-derived c-kit(+) cells to neonatal rodents with HILI improved alveolarization as evidenced by increased lung septation and decreased mean linear intercept. This was accompanied by an increase in lung vascular density, a decrease in lung apoptosis, and an increase in the secretion of proangiogenic factors. There was no difference in pulmonary vascular remodeling or the degree of pulmonary hypertension. Confocal microscopy demonstrated that 1% of total lung cells were GFP(+) cells. IT administration of BM-derived c-kit(+) cells improves lung alveolarization and angiogenesis in neonatal HILI, and this may be secondary to an improvement in the lung angiogenic milieu.

Interface between residential aged care facilities and a teaching hospital emergency department in Western Australia.

OBJECTIVE: To estimate the appropriateness of emergency department (ED) presentations by people aged>or=65 years living in residential care facilities. DESIGN, SETTING AND PARTICIPANTS: Retrospective cohort study of older residents of residential care facilities who presented to the ED of the Royal Perth Hospital, Western Australia, between January and June 2002. Data were reviewed by an expert clinical panel. MAIN OUTCOME MEASURES: Appropriateness of ED presentation, presenting complaint, involvement of a general practitioner/locum doctor prior to transfer, proportion of patients admitted to hospital from the ED, survival to discharge. RESULTS: 541 residents aged>or=65 years were transferred by ambulance to the ED, comprising 8.3% of all ED presentations of people in this age group. The mean age of the study cohort was 83.7 years (SD, 7.0 years), of which 68% were women. Of the 541 presentations, 326 (60%) resulted in hospital admission, and of these, 276 (85%) survived to hospital discharge. Musculoskeletal disorders accounted for 25% of all presentations, and 22% were falls-related; pneumonia (11% of presentations) was the single largest presenting complaint. ED attendance was deemed "inappropriate" for 71/541 cases (13.1%; 95% CI, 10.5%-16.2%); in only 25% of ED presentations was a GP/locum doctor involved prior to transfer. CONCLUSIONS: The majority of ED presentations by aged care residents were considered to be appropriate, but there was scope for improvement in coordinating care between the hospital ED and residential care institutions.