Clearance of Clara Cell Secretory Protein 16 (CC16) and Surfactant Proteins A and B from Blood in Acute Respiratory Failure

Abstract

Surfactant proteins A and B (SP-A and SP-B) enter the circulation in a manner that acutely reflects changes in pulmonary function in patients with acute respiratory failure (ARF). There is a small but significant gradient in SP-A and SP-B from arterial to mixed venous (A-V) blood, and since we have detected both proteins in urine, the kidney may be a major site of their systemic clearance. Clara cell secretory protein 16 (CC16), which leaks from the respiratory tract, is known to be freely eliminated by the kidney. Lung plasma protein levels will depend on the rates of both protein entry into and clearance from plasma. In order to study the limiting variable determining these levels, we compared plasma CC16, SP-A, and SP-B in matching A-V blood samples from 37 ARF patients with indices of lung dysfunction and glomerular filtration rate (GFR) (of plasma cystatin C and creatinine). Cystatin C, CC16, SP-A, and SP-B were reduced in mixed venous plasma (all p < 0.001) and their A-V gradients were directly related to their arterial levels (all p < 0.03). Whereas CC16, SP-A, and SP-B reflected blood oxygenation (all p < 0.05), only SP-A and SP-B were related to lung injury score (LIS) (both p < 0.05). In contrast, whereas the clearances of both CC16 and cystatin C were related to that of creatinine (p < 0.02 for both), the clearances of SP-A and SP-B were not. Our study confirms that all three lung proteins are acutely cleared from the circulation of patients with ARF (half-lives < 18 min), and we conclude that whereas the plasma concentration of CC16 depends on GFR, plasma concentrations of SP-A and SP-B reflect lung function independently of this variable.

Clara Cell Protein (CC16), a Marker of Lung Epithelial Injury, Is Decreased in Plasma and Pulmonary Edema Fluid From Patients With Acute Lung Injury

“…Patients with ALI/ARDS were significantly younger than those with CPE; however, age has not been shown to affect CC16 levels significantly. 29,45 Renal function is a significant predictor of plasma CC16 levels. 29,45 Both subject groups in the current study had moderate renal impairment, although this did not significantly differ between patients with ALI/ARDS and those with CPE.…”

“…29,45 Renal function is a significant predictor of plasma CC16 levels. 29,45 Both subject groups in the current study had moderate renal impairment, although this did not significantly differ between patients with ALI/ARDS and those with CPE. Plasma creatinine was not significantly correlated with plasma CC16 concentration, and after controlling for creatinine, plasma CC16 remained significantly lower in patients with ALI/ ARDS (data not shown).…”

Comparable effect of conventional ventilation versus early high-frequency oscillation on serum CC16 and IL-6 levels in preterm neonates

“…These findings suggest similar systemic alveolar leakage (CC16) and inflammation (IL-6) when the use of these ventilatory techniques is optimized. Serum CC16 and IL-6 in preterm neonates K Sarafidis et al Disruption of the alveolar membrane with mechanical ventilation enhances leakage of CC16 from the alveoli into the bloodstream as documented in experimental models of acute lung injury, 21 adults ventilated for acute respiratory failure 9,11 and preterm neonates with RDS. 14 Nevertheless, although all types of mechanical ventilation cause structural disruption of the alveoli, 22 damage of the alveolar-capillary barrier and protein leakage was found to be less with HFOV, at least in animal studies.…”

“…6 Nevertheless, although the lavage fluid technique may not be used after weaning off the ventilator, there are very few data regarding lung injury biomarkers in the circulation of neonates involving mainly pro-and anti-inflammatory cytokines. 7,8 Recently, Clara cell protein (CC16) has been used as peripheral blood biomarker of various lung diseases in adults, [9][10][11] children 12 and neonates. 13,14 CC16 is a lung-specific protein produced by the tracheobronchial epithelium, especially in the terminal bronchioles in which nonciliated Clara cells are localized and is believed to raise in the blood stream of subjects with pathological situations characterized by increased permeability of the alveolar-capillary barrier.…”

Serum levels of CC16, SP-A and SP-B reflect tobacco-smoke exposure in asymptomatic subjects

“…In contrast, its circulating level primarily reflects the integrity of the alveolocapillary barrier, at least in patients with acute lung injury [2,14]. Serum SP-B levels have never been evaluated in tobacco smokers.…”