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
Deformities of the renal tract in children with meningomyelocele and hydrocephalus, compared with those of children showing no such central nervous system deformities. Britishyournal of Urology, 42, 152.
ABSTRACT:Complications from meconium aspiration syndrome (MAS) remain significant despite a variety of therapeutic interventions. Clara cell protein (CC10) is a novel anti-inflammatory agent that can also inhibit phospholipase A 2 (PLA 2 ) (an important component of meconium). The present study examined whether administration of recombinant human CC10 (rhCC10) would reduce inflammation and improve lung function in a piglet model of MAS. Following meconium instillation, piglets exhibited significant physiologic dysfunction that improved significantly after surfactant administration. Analysis of tracheal aspirates revealed significant increases in both tumor necrosis factor (TNF) ␣ and interleukin (IL)-8 after meconium instillation. rhCC10-treated animals had significantly lower TNF-␣ levels at 24 h (561 Ϯ 321 versus 1357 Ϯ 675 pg/mL, p Ͻ 0.05) compared with saline controls. There were no differences between rhCC10-treated and untreated groups with respect to other measured physiologic variables or inflammatory markers, including secretory PLA 2 activity. Histologic analyses revealed marked inflammatory infiltrates and thickened alveolar walls, but no significant differences among rhCC10 and control animals. Newborn piglets with MAS have significant physiologic dysfunction, marked inflammatory changes and histologic abnormalities, which was partially counteracted by a single dose of exogenous surfactant and rhCC10.
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