The association between the anti-inflammatory protein CC10 and smoking status among participants in a chemoprevention trial.

CC10, the secretory product of bronchiolar Clara cells, is infrequently expressed in non-small cell lung cancer (NSCLC), and its overexpression in NSCLC cell lines results in a less malignant phenotype. CC10 levels in bronchoalveolar lavage fluid (BAL) and serum are significantly lower in current smokers than healthy nonsmokers, but the effect of long-term smoking cessation on CC10 is unknown. We measured CC10 in baseline BAL and plasma collected from current (n = 81) and former (n = 23) smokers participating in a chemoprevention trial. Former smokers had significantly higher plasma CC10 levels compared with current smokers [mean, 62.1 ng/mL (95% CI, 43.0-81.2); range, 23.0-175.0 ng/mL for former smokers; and mean, 37.1 ng/mL (95% CI, 29.8-44.4); range, 5.0-171.0 ng/mL for current smokers; P < 0.001]. BAL CC10 levels also trended in the same direction. A significant positive correlation was found between CC10 plasma and BAL levels. After adjustment for age, sex, and pack-years of cigarette consumption, former smokers had 1.70 (95% CI, 1.23-2.36) times higher plasma CC10 levels than current smokers (P < 0.01), whereas former smokers also had nonsignificantly higher baseline BAL CC10 levels compared with current smokers [adjusted mean ratio (95% CI), 1.60 (0.92-2.80), P = 0.094 and 1.35 (0.86-2.10), P = 0.193 for the absolute and normalized BAL CC10, respectively]. These results show that sustained smoking cessation is associated with higher plasma CC10 levels, suggesting that at least some of the damage associated with tobacco smoke may be repaired by long-term smoking cessation.

Recombinant human Clara cell secretory protein in acute lung injury of the rabbit: effect of route of administration.

OBJECTIVE: To test the hypothesis that intratracheal instillation of Clara cell secretory protein (CC 10) to the lung may afford greater protection than intravenous administration from ventilator-induced lung inflammation. DESIGN: Interventional laboratory study. SETTING: An academic medical research facility in northeastern United States. SUBJECTS: Sedated, lavage-injured juvenile rabbits. INTERVENTIONS: A total of 18 juvenile rabbits were anesthetized, ventilated, injured with saline lavage (Pao2 of <100 mm Hg; respiratory compliance of <0.50 mL.cm H2O.kg and <50% baseline), and randomized to receive intratracheally administered surfactant plus no recombinant human CC 10 (rhCC 10, control), intravenous rhCC 10, or intratracheal rhCC 10. MEASUREMENT AND MAIN RESULTS: Arterial blood chemistry and pulmonary mechanics were monitored; plasma and urine were collected serially. After 4 hrs of ventilation, lungs were lavaged and harvested. Surfactant function was analyzed from bronchoalveolar lavage samples (surfactometry); rhCC 10, interleukin-8, and lung myeloperoxidase concentrations were measured. Pao2, oxygenation index, ventilatory efficiency index, and respiratory compliance were not different across time or group beyond injury. Surfactometry data identified no differences as a function of group or time. Plasma, bronchoalveolar lavage, and lung interleukin-8 concentrations, lung myeloperoxidase concentrations, and inflammatory cell counts in the alveolar and interstitial spaces of intravenous and intratracheal groups were lower than in the control group (p < .05) but not statistically different from each other. Concentrations of rhCC 10 in lung, bronchoalveolar lavage, and plasma were greater in the intratracheal group than in the intravenous group (p<.05). Urine rhCC 10 concentrations were greater for the intravenous group than for the intratracheal group (p<.05) at 1, 3, and 4 hrs after treatment. No group differences in histomorphometry were noted. CONCLUSIONS: Both intravenous and intratracheal rhCC 10 delivery, after surfactant therapy, effectively decrease lung inflammation vs. surfactant alone. While supporting the physiologic profile, intratracheal instillation results in greater, maintained lung and plasma rhCC 10 pools compared with intravenous administration. As such, intratracheal instillation of rhCC 10 may afford more prolonged protection against lung inflammation than intravenous administration.

A malignant aldosteronoma.

OBJECTIVE: To describe a case of primary aldosteronism due to an adrenocortical carcinoma (ACC) and highlight the need for thorough long-term follow-up. METHODS: We present the clinical, laboratory, radiologic, and pathologic findings in a patient with ACC and review the related literature. RESULTS: A 52-year-old woman with a history of hypertension and hypokalemia was referred for evaluation of a 6-cm adrenal mass. Her biochemical studies revealed a serum aldosterone-to-renin ratio of 52 without evidence of cortisol, catecholamine, or androgen excess. She underwent surgical resection of this mass, and histologic analysis showed a focally brisk mitotic rate but no evidence of capsular or vascular invasion. In light of these findings, the biologic nature of the tumor was difficult to predict. Thus, it was thought to be an adrenocortical neoplasm. The patient underwent follow-up clinically, biochemically, and with interval computed tomography. Nine years later, hypertension and hypokalemia redeveloped, and she was found to have metastatic ACC. CONCLUSION: ACC can generally be reliably diagnosed; however, in some cases, the true biologic behavior is difficult to predict. We emphasize the importance of careful clinical, biochemical, and radiologic surveillance in these difficult cases because surgical resection provides the best opportunity for cure in patients with adrenal cancer.

Recombinant human uteroglobin/CC10 inhibits the adhesion and migration of primary human endothelial cells via specific and saturable binding to fibronectin.

Uteroglobin (UG) or Clara Cell 10 kDa protein (CC10) is a small, stable, epithelial secretory anti-inflammatory protein. Uteroglobin has been shown to inhibit neointimal formation in vivo after balloon angioplasty through an unknown mechanism. An interaction between UG and plasma fibronectin (Fn) has been demonstrated in mice. Since Fn plays a key role in endothelial cell (EC) migration and angiogenesis, we investigated whether recombinant human UG (rhUG) affects EC migration via Fn binding. In this report, we show a saturable binding of rhUG to Fn depending on Fn conformation and that rhUG is covalently cross-linked to Fn by transglutaminase (TGase). Additionally, our study highlights that rhUG can also bind to exogenously added or self-secreted Fn on the membrane of human primary microvascular endothelial cells (HMVEC), although these complexes are weakly associated with the plasmalemma. Upon the interaction with Fn in solid phase, rhUG strongly inhibits HMVEC attachment on Fn, but not on other ECM proteins. Consequently, rhUG also inhibits cell migration in a dose dependent fashion (I.C.50 = 65 nM) and hinders the "wound healing" in vitro. The small size, stability and human tolerability of rhUG suggest that rhUG in slow-release form or genetically delivered could be used in humans to modulate cell/Fn interactions in the context of tumor microenvironment or in the context of inflammation and fibrosis.

The safety, pharmacokinetics, and anti-inflammatory effects of intratracheal recombinant human Clara cell protein in premature infants with respiratory distress syndrome.

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, double-blinded, 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 = 7) or 1.5 mg/kg (n = 8) or 5 mg/kg (n = 7) rhCC10 within 4 h of surfactant treatment. Pharmacokinetic analyses demonstrated that the serum half-life 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 < 0.0002), neutrophil counts (p < 0.001), and total protein concentrations (p < 0.01) and tended to have decreased IL-6 (p < 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.

Endocrine abnormalities in patients with central serous chorioretinopathy.

PURPOSE: To investigate and to identify endocrine and metabolic abnormalities in patients with central serous chorioretinopathy (CSCR). DESIGN: Observational case series. PARTICIPANTS: Twenty-four patients with CSCR. METHODS: Serum and urinary catecholamines, glucocorticoids, mineralocorticoids, serum testosterone, and thyroid-stimulating hormone (TSH) function were evaluated prospectively. RESULTS: Fifty percent (12 of 24) of patients with active acute CSCR showed elevated 24-hour urine cortisol or tetrahydroaldosterone levels. Serum aldosterone levels were low in 7 of 24 (29.1%) patients. Single morning plasma catecholamine levels were elevated in 7 of 24 patients, although 24-hour urine metanephrines (catecholamine breakdown products) were normal. Serum testosterone and TSH levels were normal in nearly all (23 of 24) patients. CONCLUSION: Many patients with acute CSCR have elevated 24-hour urine corticosteroids, which may contribute to the pathogenesis of the disorder. Endogenous mineralocorticoid dysfunction is a newly described feature of CSCR.