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Objective A low expression of club cell secretory protein (CC16) and high levels of proinflammatory cytokines at preterm birth are associated with airway inflammation and more severe neonatal lung disease. The present study aimed to investigate if low levels of CC16, proinflammatory cytokines and vascular endothelial growth factors (VEGF) in tracheal aspirate early after birth were associated with lung function impairment at school age.Patients and methods Participants were 20 children, born very preterm (median gestational age 25+3 weeks+days, IQR: 24+1–27+0 weeks+days), who had tracheal aspirates collected during mechanical ventilation in their first day of life. CC16, cytokines, VEGF and matrix metalloproteinase-9 were measured in the tracheal aspirate and later correlated to results from advanced lung function measurements at 12 years of age.Results Low levels of CC16 and high levels of the proinflammatory cytokines IL-1β and TNF-α in tracheal aspirate were associated with airway obstruction at school age but not with other lung function parameters. The correlation with airway obstruction was even stronger when the ratio between the respective proinflammatory cytokine and CC16 was used. In addition, low levels of VEGF and CC16 were associated with impaired diffusion capacity of the lung.Conclusions An imbalance in inflammatory mediators and growth factors in the lungs at birth may have consequences for airway function and vasculature at school age in preterm born children.

During development of the nigrostriatal dopamine system, a patchy and a diffuse type of striatal innervation pattern can be seen. It has been suggested that when fetal dopaminergic neurons, obtained from the ventral mesencephalon (VM), are grafted adjacent to mature striatal tissue, only the diffuse growth is induced. Intraocular grafting studies have indicated that the dopaminergic growth pattern might be influenced by the age of the target area, the lateral ganglionic eminence (LGE). In this study VM grafts were allowed to innervate LGE grafts of different ages. Fetal VM was implanted next to 2-wk-old or 26-day-old striatal in oculo grafts, and the resulting dopaminergic innervation of the striatal grafts was studied using tyrosine hydroxylase (TH) immunohistochemistry. In striatal grafts receiving innervation at the age of 2 wk in oculo, a patchy TH-immunoreactive growth pattern was found, while in striatal grafts innervated at the age of 26 days mainly the diffuse growth pattern was seen. This implies that grafted striatum reached maturity at approximately 1 mo of age. The age of the dopaminergic neurons at dissection and grafting was also studied concerning the ability to induce patchy growth into mature striatum. Thus, VM dissected from 13- and 18-mm fetuses was implanted to either 4-mo-old LGE (grafted in sequence) or to LGE from the same fetus (grafted simultaneously) as controls. TH-positive innervation of striatal tissue, evaluated 4 wk after implantation of VM, revealed a patchy growth pattern in LGE grafted simultaneously with 13- and 18-mm VM. However, when the striatum was mature at the time of innervation, diffuse growth was observed in striatum innervated by VM dissected from 13-mm fetuses. Interestingly, patchy growth was noted in striatal areas close to VM grafts when the dopaminergic neurons were derived from older fetuses (CRL 18 mm). Furthermore, potassium-induced dopamine release was greater in striatal grafts exhibiting the patchy growth than those showing the diffuse pattern of innervation. In conclusion, patchy dopaminergic growth can be induced in mature striatal tissue by grafting VM from older fetuses. Functionally, potassium-evoked dopamine release is enhanced in dopaminergic patches. These results have implications in terms of finding ways to induce patchy growth when grafting to the mature striatum of patients suffering from Parkinson's disease.

In animal models of Parkinson's disease, transplanted fetal mesencephalic dopaminergic neurons can innervate the dopamine-depleted host brain, but it is unclear why large portions of the host striatum are left uninnervated. During normal development, the dopaminergic innervation first occurs in the form of a dense patchy pattern in the striatum, followed by a widespread nerve fiber network. Using intraocular double grafts we have investigated dopaminergic growth patterns initiated when ventral mesencephalic grafts innervate striatal targets. The fetal lateral ganglionic eminence was implanted into the anterior eye chamber. After maturation in oculo, fetal ventral mesencephalon was implanted and placed in contact with the first graft. In other animals the two pieces of tissue were implanted simultaneously. Tyrosine hydroxylase (TH) immunohistochemistry revealed a pattern of dense TH-positive patches throughout the total volume of the striatal grafts in simultaneously transplanted cografts, while a widespread, less dense, pattern was found when mature striatal transplants were innervated by fetal dopaminergic grafts. To investigate which type or types of growth patterns that developed after grafting to striatum in situ of an adult host, fetal ventral mesencephalic tissue was implanted into the lateral ventricle adjacent to the dopamine-lesioned striatum. After maturation of the mesencephalic graft, the fetal lateral ganglionic eminence was implanted into the reinnervated part of the host striatum. TH immunohistochemistry revealed a few nerve fibers within the striatal graft and the growth pattern was of the widespread type. In conclusion, grafted dopaminergic neurons preferably innervate mature striatum with a widespread sparse nerve fiber network, while the innervation of the immature striatum occurs in the form of dense patches. Furthermore, when the patchy pattern is formed, the total volume of the striatal target is innervated while growth of the widespread type terminates prior to reaching distal striatal parts. Thus, the growth pattern seems essential to the final volume that is innervated. Once the widespread growth pattern is initiated, the presence of immature striatum does not change the dopaminergic growth pattern.