| Bronchopulmonary dysplasia(BPD), as known as chronic lung disease(CLD) before, is a chronic disorder characterized with chronic respiratory distress and pulmonary dysfunction. Along with there have being more and more extremely preterm neonates and very preterm neonates rescued successfully, the incidence of BPD is a growing trend, especially in the very low birth weight infants(VLBW) among which20～40%infants get the disease. BPD develops in the neonatal period and maintains very long, for the most they will be afflicted during whole life. The disease often happens following the respiratory, inhalation syndrome, neonatal pneumonia, which present tachypnea, hypoxemia, acidosis, three depressions sign, cyanosis and respiratory and therefore receive respiratory support therapy. After a long time they can not wean with oxygen and ventilator, BPD happens. The little patients grow stunt, death often follows in a few weeks while they can survive several years even until early adult, they would be cursed by again and again rehospitalization for repeatedly pulmonary infections, cardiopulmonary dysfunction and other distresses which in fine lead to death.The typical clinical pathological manifestations are like that:early stage starts from the destriction of alveolar epithelial cells and capillary endothelial cells companied with stromal and perivascular edema, the small bronchi injury, squamous Cell metaplasia, ciliated epithelial cell apoptosis and necrosis, smooth muscle hypertrophy. Pathogenesis progresses quickly followed by the invasion of inflammatory cells, macrophages, fibroblasts and collagen depositon, interstial thickening, bronchial damage so that there form local atelectasis and emphysema.BPD is a disease syndrome involving multiple factors. The development of the respiratoy system is divided into two periods included with embryonic and postnatal. At gestational age24weeks it is the small tube period, the alveoli precursor, the bronchioles, the precursor of the capillaries, mucous glands, bronchial stent structure start to form. After28weeks embryonic lung progress into the sac period involving the formation of alveoli and alveoli begins secrete pulmonary surfactant, so that real respiratory function begins to form. However, the accomplishments of the structure and function of alveolar were gotten until about8years old. Therefore, during the duration any factors that abrupt the process can cause serious damage to the structure and function development, especially in the neonatal period, all relevant factors can lead to BPD.Bone marrow-derived mesenchymal stem cells(BMSC) are from bone marrow stromal stem cells. BMSC can support the function of bone marrow-derived hematopoietic stem cells. However, the most important function of BMSC is differentiation into bone cells, cartilage cells and fat cells, even then under some inducing conditions into nerve cells, alveolar epithelial cells, cardiac muscle cells, liver cells and other organs cell. BMSC are pocessed with some immunophenotype as MHCl+、MHC2-、CD40-、CD80-and no immunogenicity. On the other hand, BMSC can activate and induce peripheral T cells and then play the roles of immune regulations. Eventually, BMSC can be obtained easily in not animal experiments also in clinical donor or self body drawn. Substituting cells cultured in vitro can keep homogenous, what’s more, under specific induced stimulation BMSC also have a characteristics of multi-directional differentiation potent. In a word, as a multiple potential stem cells, the obtain of BMSC is easy and low cost, BMSC should have broad prospects.Based on these findings, we raised mice exposed to60%oxygen from birth, the control group mice were exposed to21%oxygen (air). the mice general condition were recorded including body weight. On21days after birth the mice were sacrificed and lung tissue were obtained. In the process of feeding mice BPD model, we found even healthy mice (i.e. air control mice) grew slowly in the first3days after birth. throughout the21days-feeding period, the hyperoxia group and the air control group mice shared weight gain, but the hyperoxia group mice grew generally lower down in compared with the normal air control group, showing significant difference at21days of age. Furthermore, the hyperoxia group mice were lack of energy, exhibiting poor general condition. Through7days exposure the hyperoxia group and the air control group appeared more obvious differences, in comparison with the control mice the hyperoxia group were poorer in subcutaneous fat, the general reaction, oxygen intolerance, fur sleeky. On21day-old the hyperoxia group were poorer. There demonstrating the symptoms of poor feeding, shaggy, arch back, head, breathing audible and nasals, oxygen from toleration, shortness of breath, cyanosis, pale skin, and even convulsions, while the control group grew lively. This is more in line with human BPD infant malnutrition. With the rest of alveolarization followed by the reduce of gas exchange, the body could not meet demand for oxygen. At the same time, cytotoxic reactive oxygen species damaged the cell metabolism, leading to malnutrition and growth retardation. In compared with the air group, no significant quantitative changes happened to the hyperoxia group on2-day age, with the distal hypertrophic alveolar and interstitial tissue. On7-day age the alveolar morbidity of the hyperoxia group increased and lung parenchyma appeared focal thickening. As the disease progresses, on21-day age, the hyperoxia group showed histopathological features similar to human BPD. P7, P21, RAC were reduced by34%(P<0.01),33%(P<0.01).We analyzed the surface immunophenotype and found BMSC family were positive for CD105and CD106whereas negative for CD34and CD45. The results of co-culture of BMSC with the hyperoxia injury lung cells manifested that SP-C and proteins(specific markers for typeⅡ alveolar epithelial cells). Conversely, BMSC alone did not express those, neither co-cultured with normoxic lung cells. The results reveal injured lung could promte BMSC migration in vitro.In situ hybridization indicated the presence of Y-chromosome cells in the corner of alveolar. The results indicated intraperitoneal injection of exogenous BMSC can migrate to injury lung. Immunofluorescence verified that SP-C and BMSC are expressed in BPD mice lung. Furthermore, given BMSC, the expression were increased significantly. Treated with BMSC the survival rate of BPD mice increased. We studied RAC and found more aveolarization with injection of BMSC. Trichrome stain indicated that BMSC reduced the severity of pulmonary fibrosis around the alveoli and the airway. Real time qPCR and ELISA also revealed that the group with BMSC treatment TGF β1,TIMP-1,collagen1α expressed decreasedly significantly and the plasma concentration of IL-land TNF α decreased significantly.MiRNA regulate lung septation and play an important role on the development of BPD. Exogenous BMSC can migrate to injury lung and improve the destroyed lung structure. |
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