No abstract

Despite the widespread use of exogenous surfactant, acute and chronic lung injury continues to be a major cause of morbidity in preterm infants. CC10 is a protein produced by Clara cells that inhibits phospholipase A 2 and has anti-inflammatory and antifibrotic properties. We studied whether intratracheal (IT) recombinant human Clara cell protein (rhCC10) could safely minimize lung injury in a newborn piglet model of acute lung injury. Twenty-nine newborn piglets were given Survanta and then ventilated for 48 h receiving the following: room air (group 1); 100% O 2 (group 2); or 100% O 2 and 25, 5, or 1 mg/kg (groups 3, 4, and 5, respectively) of IT rhCC10 (diluted to 2 mL/kg with saline) at time 0. Laboratory studies, oxygen ratios, static pressure-volume curves, bronchoalveolar lavage (for inflammatory markers), and histologic analyses were performed over the 48-h study period. Pulmonary compliance and oxygenation were significantly improved in animals receiving 5 mg/kg IT rhCC10 compared with room air and 100% O 2 controls (p Ͻ 0.004 and p Ͻ 0.05, respectively, ANOVA). Reductions in inflammatory markers were seen in animals receiving rhCC10, although changes did not reach statistical significance. No significant toxicity was noted. rhCC10 appeared safe and improved pulmonary function in this newborn piglet model of hyperoxic lung injury. We speculate that rhCC10 may represent a promising therapy for the prevention of lung injury in preterm infants. Bronchopulmonary dysplasia continues to be a significant problem for the preterm infant despite improvements in neonatal intensive care. Although the use of antenatal steroids and exogenous surfactant has resulted in decreased severity of BPD, the prevalence of BPD in the preterm population has actually increased. BPD is a multifactorial disease process that is the end result of an immature, surfactant-deficient lung that has been exposed to hyperoxia, mechanical volutrauma, and infection. These forces initiate a cascade of pro-inflammatory cytokines that lead to the development of significant inflammatory changes and chronic lung injury.CC10 is produced by the nonciliated cells of the tracheobronchial epithelial tree and is thought to have numerous anti-inflammatory properties. It has been shown to play a significant role, both in vitro and in vivo, in modulating inflammation (1-5). CC10, also known as uteroglobin, inhibits sPLA 2 (2, 6), an enzyme that degrades surfactant and facilitates prostaglandin biosynthesis (through the cleavage of arachidonic acid from cell membrane phospholipids). In vitro, CC10 has been shown to inhibit neutrophil and phagocyte chemotaxis (3) and IL-stimulated release of numerous cytokines in human blood lymphocytes (tumor necrosis factor-␣, IL-1␤, and interferon-␥) (4). CC10 also inhibits the formation of the proinflammatory fibronectin/IgA complex that may mitigate fibrotic changes in the lung (7). Further in vivo evidence of these ABSTRACT509

Abstract. To study the influence of cAMP on cellular responses to nerve growth factor (NGF) and to use elevation of intracellular cAMP to probe the NGF mechanism, cultured PC12 pheochromocytoma cells were exposed to forskolin and cholera toxin. As in other cell types, the latter agents greatly increased PC12 cell cAMP levels. Such treatment also brought about a reversible, dose-dependent suppression of NGF-promoted regeneration of neurites. In support of the role of cAMP in this effect, regeneration blockage by forskolin was potentiated by phosphodiesterase inhibitors. When tested on NGF-stimulated initiation of process outgrowth, cholera toxin and forskolin exerted a dual effect. As in previous studies, these drugs, when applied along with NGF, significantly enhanced the initial formation of short cytoplasmic extensions. However, after •3 d of NGF exposure, at which time such extensions begin to acquire the morphological and ultrastructural features of neurites, these agents suppressed process outgrowth. That is, the neurites were fewer in number, significantly less branched, and much shorter than in control cultures. Such changes also occurred when these drugs were added to cultures that had been pretreated with NGF alone. Whereas forskolin and cholera toxin affect the formation and regeneration of neurites, these drugs did not interfere with the short-latency, transient changes in surface morphology that are triggered by NGF, nor did they inhibit transcription-dependent priming. In contrast, the rapidly occurring NGF-induced phosphorylation of tyrosine hydroxylase was suppressed. Moreover, forskolin and cholera toxin rapidly and selectively blocked the NGF-promoted phosphorylation of a set of microtubule-associated proteins known as chartins. Previous observations have suggested a causal relationship between NGF-induced chartin microtubuleassociated protein phosphorylation and the formation and outgrowth of neurites. This is supported by the present data and provides a possible mechanism whereby elevated cAMP may interfere with neurite growth and regeneration.