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Pleural fluid (PF) proteins either derive from serum by diffusion or are locally secreted within the pleural space. Another hypothetical origin is a leakage of lung secretory proteins across the visceral pleura. To test this hypothesis, we investigated the occurrence, sources, and determinants in PF of CC16, a small-size and readily diffusible protein of 16 kDa secreted by bronchiolar Clara cells. CC16 concentration was determined by a sensitive latex immunoassay in serum and PF of 117 subjects (86 exudates and 31 transudates) and, for purpose of comparison, in ascites samples from another group of 38 subjects (7 exudates and 31 transudates). CC16 was also studied in serum and PF of normal rats and in rats with pleural exudate induced by alpha-naphthyl-thiourea (ANTU). The levels of CC16 in PF and ascites were highly correlated with that in serum, suggesting a diffusional exchange across the pleural/blood and peritoneal/blood barriers. Whereas CC16 occurs at similar levels in ascites and serum, the protein was found to be more concentrated in PF than in serum in both humans (geometric mean in microg/L, 26.2 versus 14.6, p < 0.0001) and rats (213 versus 16.2, p < 0.001). A local synthesis of CC16 appeared unlikely in view of the lack of CC16-immunostaining in pleura of both species. The only plausible explanation for these findings is that CC16 in PF originates from two sources: diffusion from plasma and a leakage from the lung into the pleural space across the semipermeable visceral pleura. This interpretation is supported by a markedly increased leakage of CC16 in experimental exudates induced by ANTU and the finding of high CC16 concentrations in human transudates associated with congestive heart failure, two conditions wherein PF has been shown to arise from the interstitial spaces of the lung.

Clara cell protein (CC-16, also designated CC-10) is synthesized by the bronchiolar epithelium and has been suggested as an inhibitor of phospholipase A(2) (PLA(2)) activity. Therefore, CC-16 is a candidate for controlling inflammatory events in the lung. Because CC-16 amounts and function may be altered in fibrosing lung diseases in which bronchiolar injury has been reported, it was measured in alveolar fluids and sera. Secretory PLA(2) activity in alveolar fluids and the influence of CC-16 on platelet-derived growth factor-induced human fibroblast chemotaxis and cytosolic PLA(2) activity were also explored. CC-16 content was decreased in alveolar fluids from idiopathic pulmonary fibrosis (IPF: 1.3 +/- 0.1 mg/L) and bleomycin lung (1.1 +/- 0.2 versus 2.1 +/- 0.2 mg/L in controls, p < 0.05), whereas there was a three- to ninefold increase in secretory PLA(2) activity (p < 0.05 versus controls). CC-16 inhibited fibroblast chemotaxis in a dose-dependent manner (90% inhibition at 30 mu g/ml CC-16). This inhibition was reversed by reducing CC-16. CC-16 was also able to lower fibroblastic cytosolic PLA(2) activity by 50% in vitro. In summary, CC-16 is able to inhibit fibroblast chemotaxis in vitro by mechanisms that may be related to a blockage of cytosolic PLA(2) activity. It can be postulated that CC-16 deficiency may contribute to fibroblast burden activity in fibrosing lung diseases.