Clara Cell Secretory Protein Oxidation and Expression in Premature Infants Who Develop Bronchopulmonary Dysplasia

Ramsay, Patricia L; DeMayo, Francesco J.; Hegemier, Suzanne; Wearden, Mary E; Smith, Charles V.; Welty, Stephen E.

doi:10.1164/ajrccm.164.1.2008022

Cited by 90 publications

(72 citation statements)

References 34 publications

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“…Average elimination half-lives were 11.6 h in the 1.5-mg/kg group and 9.9 h in the 5.0-mg/kg group, consistent with results from animal models (18).…”

Section: Patientssupporting

confidence: 86%

“…CC10 concentrations have been demonstrated to correlate negatively with the concentration of inspired oxygen required by preterm infants with respiratory distress syndrome (RDS) (17). Most recently, Ramsey et al (18) demonstrated that not only were CC10 concentrations lower in TAF from infants who either died or developed BPD, but also the limited amount of available CC10 was oxidized and demonstrated less immunoreactivity relative to controls.…”

mentioning

confidence: 99%

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Safety, Pharmacokinetics, and Anti-inflammatory Effects of Intratracheal Recombinant Human Clara Cell Protein in Premature Infants with Respiratory Distress Syndrome

et al. 2005

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Clara cell 10-kD protein (CC10) is a potent anti-inflammatory protein that is normally abundant in the respiratory tract. CC10 is deficient and oxidized in premature infants with poor clinical outcome (death or the development of bronchopulmonary dysplasia). The safety, pharmacokinetics, and anti-inflammatory activity of recombinant human CC10 (rhCC10) were evaluated in a randomized, placebo-controlled, doubleblinded, multicenter trial in premature infants with respiratory distress syndrome. A total of 22 infants (mean birth weight: 932 g; gestational age: 26.9 wk) received one intratracheal dose of placebo (n ϭ 7) or 1.5 mg/kg (n ϭ 8) or 5 mg/kg (n ϭ 7) rhCC10 within 4 h of surfactant treatment. Pharmacokinetic analyses demonstrated that the serum halflife was 11.6 (1.5 mg/kg group) and 9.9 h (5 mg/kg group). Excess circulating CC10 was eliminated via the urine within 48 h. rhCC10-treated infants showed significant reductions in total cell count (p Ͻ 0.0002), neutrophil counts (p Ͻ 0.001), and total protein concentrations (p Ͻ 0.01) and tended to have decreased IL-6 (p Ͻ 0.07) in tracheal aspirate fluid collected over the first 3 d of life. Infants in all three groups showed comparable growth. At 36 wk postmenstrual age, five of seven infants were still hospitalized and two of seven infants were receiving oxygen in the placebo group compared with two of seven hospitalized and one of seven receiving oxygen in the 1.5-mg/kg group and four of six hospitalized and three of six receiving oxygen in the 5-mg/kg group. A single intratracheal dose of rhCC10 was well tolerated and had significant anti-inflammatory effects in the lung. Multiple doses of rhCC10 will be investigated for efficacy in reducing pulmonary inflammation and ameliorating bronchopulmonary dysplasia in future studies. Bronchopulmonary dysplasia (BPD) affects 20 -60% of all premature, very low birth weight infants. It is associated with substantial morbidity and mortality as well as extremely high health care costs. Although the widespread use of exogenous surfactant and antenatal steroid therapy has reduced the overall severity of BPD, the prevalence of this condition has increased with improved survival of very low birth weight infants. BPD is a multifactorial disease process that is the end result of an immature, surfactant-deficient lung that has been exposed to hyperoxia, mechanical ventilation, and infection. These forces initiate a cascade of proinflammatory cytokines that lead to the development of significant inflammatory changes and chronic lung injury.Clara cell 10-kD protein (CC10) is also known as uteroglobin. It is a small homodimeric secretory protein that is produced by mucosal epithelial cells (1). In humans, Clara cells are the main site of CC10 production (located in the airways), and several other organs synthesize smaller amounts of mRNA encoding this protein (2-4). CC10 also circulates in the blood

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“…Average elimination half-lives were 11.6 h in the 1.5-mg/kg group and 9.9 h in the 5.0-mg/kg group, consistent with results from animal models (18).…”

Section: Patientssupporting

confidence: 86%

mentioning

confidence: 99%

Safety, Pharmacokinetics, and Anti-inflammatory Effects of Intratracheal Recombinant Human Clara Cell Protein in Premature Infants with Respiratory Distress Syndrome

et al. 2005

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“…SCGB1A1 has immune modulatory properties Zhang et al, 2000), and a decrease of SCGB1A1 is observed in lung diseases such as COPD and bronchopulmonary dysplasia. Thus, a loss of SCGB1A1 may contribute to the pathogenesis of these disorders (Ramsay et al, 2001;Thomas et al, 2010;Tsoumakidou et al, 2010). In contrast to Cebpa DLE mice, Cebpa…”

Section: Developmental Dynamicsmentioning

confidence: 99%

Airway epithelial cell differentiation during lung organogenesis requires C/EBPα and C/EBPβ

Roos

Berg

Barton

et al. 2012

Developmental Dynamics

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Background: CCAAT/enhancer‐binding protein (C/EBP)α is crucial for lung development and differentiation of the pulmonary epithelium. Conversely, no lung defects have been observed in C/EBPβ‐deficient mice, although C/EBPβ trans‐activate pulmonary genes by binding to virtually identical DNA‐sequences as C/EBPα. Thus, the pulmonary phenotype of mice lacking C/EBPβ could be explained by functional replacement with C/EBPα. We investigated whether C/EBPα and C/EBPβ have overlapping functions in regulating lung epithelial differentiation during organogenesis. Epithelial differentiation was assessed in mice with a lung epithelial–specific (SFTPC‐Cre‐mediated) deletion of C/EBPα (CebpaΔLE), C/EBPβ (CebpbΔLE), or both genes (CebpaΔLE; CebpbΔLE). Results: Both CebpaΔLE mice and CebpaΔLE; CebpbΔLE mice demonstrated severe pulmonary immaturity compared to wild‐type littermates, while no differences in lung histology or epithelial differentiation were observed in CebpbΔLE mice. In contrast to CebpaΔLE mice, CebpaΔLE; CebpbΔLE mice also displayed undifferentiated Clara cells with markedly impaired protein and mRNA expression of Clara cell secretory protein (SCGB1A1), compared to wild‐type littermates. In addition, ectopic mucus‐producing cells were observed in the conducting airways of CebpaΔLE; CebpbΔLE mice. Conclusions: Our findings demonstrate that C/EBPα and C/EBPβ play pivotal, and partly overlapping roles in determining airway epithelial differentiation, with possible implications for tissue regeneration in lung homeostasis and disease. Developmental Dynamics 241:911–923, 2012. © 2012 Wiley Periodicals, Inc.

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“…CCSP concentrations have been demonstrated to correlate negatively with the concentration of inspired oxygen required by preterm infants with RDS [64]. In a prospective study, CCSP levels in tracheal aspirates were lower from day one after birth in infants who developed BPD compared to those who did not [65].…”

Section: Clara Cell Secretory Proteinmentioning

confidence: 97%

Advances in emerging treatment options to prevent bronchopulmonary dysplasia

Ling

Greenough

2017

Expert Opinion on Orphan Drugs

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Introduction: Bronchopulmonary dysplasia (BPD) is common sequaelae of premature birth.It can be complicated by the development of pulmonary hypertension (PH), which significantly increases mortality. Areas covered: The aim of this review is to evaluate emerging drug therapies for prevention and treatment of BPD and associated PH. These include superoxide dismutase, macrolides, Clara secretary cell protein, -1 protease inhibitors, pentoxifylline, melatonin, inositol, N-acetyl cysteine, allopurinol, cimetidine, pulmonary vasodilators and mesenchymal stem cells (MSC). We have also included discussion on longer standing therapies such as corticosteroids, caffeine and vitamin A.Expert opinion: Corticosteroid administration systemically, but not by inhalation, caffeine and vitamin A reduce BPD. Enhancing endogenous anti-oxidant mechanisms through supplementation with superoxide dismutase or Clara cell secretory protein has yielded encouraging results. Azithromycin, a macrolide used to treat Ureaplasma infection, also has anti-inflammatory properties and has been shown to reduce BPD. Sildenafil reduces the echocardiographic markers of pulmonary hypertension associated with BPD, but has not been shown to prevent BPD. In animal models and a small phase one study MSC administration has resulted in promising results. Appropriately powered studies with long term outcomes are required to assess the efficacy of all these treatments.3

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Clara Cell Secretory Protein Oxidation and Expression in Premature Infants Who Develop Bronchopulmonary Dysplasia

Cited by 90 publications

References 34 publications

Safety, Pharmacokinetics, and Anti-inflammatory Effects of Intratracheal Recombinant Human Clara Cell Protein in Premature Infants with Respiratory Distress Syndrome

Safety, Pharmacokinetics, and Anti-inflammatory Effects of Intratracheal Recombinant Human Clara Cell Protein in Premature Infants with Respiratory Distress Syndrome

Airway epithelial cell differentiation during lung organogenesis requires C/EBPα and C/EBPβ

Advances in emerging treatment options to prevent bronchopulmonary dysplasia

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