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* From the University of California, San Francisco, Cardiovascular Research Institute, San Francisco, CA.
Correspondence to: Michael A. Matthay, MD, FCCP, Cardiovascular Research Institute, 505 Parnassus Ave, HSW-825, San Francisco, CA 94143-0130; e-mail: mmatt{at}itsa.ucsf.edu
Our laboratory has reported previously that endogenous and exogenous ß-adrenergic agonist stimulation can upregulate the rate of alveolar liquid clearance in several species, including sheep, dogs, rats, and mice as well as in the ex vivo human lung.1 2 3 Recently, we have also investigated catecholamine-independent mechanisms that can upregulate vectorial sodium and fluid transport across the alveolar epithelium.4 5 6 Other investigators have also investigated catecholamine-dependent and independent mechanisms.7 8
Because keratinocyte growth factor (KGF) prevents acute lung injury in several experimental models,9 10 we investigated the capacity of KGF to increase alveolar epithelial fluid transport. The studies were designed to determine the time-dependent effects of KGF and to relate the physiologic effects to morphologic findings.
Materials and Methods
Rats were instilled by the intratracheal route with either KGF (5 mg/kg) or saline solution (control rats). Several studies were carried out subsequently at 48, 72, 120, and 240 h. First, the in vivo effect of KGF on alveolar epithelial type II cell mitogenesis was determined by using bromodeoxyuridine (BrdU) and a specific alveolar epithelial type II cell monoclonal antibody (courtesy, L. Dobbs). Alveolar fluid clearance was studied in rats previously instilled with KGF or saline solution (control rats). In addition, terbutaline (10-4 M) was instilled into KGF-treated rats as well as the saline solution control rats at 72 h to determine if alveolar fluid clearance could be further increased after KGF-induced proliferation of alveolar epithelial type II cells.
To determine the number of alveolar epithelial type II cells at each time point, the total number of BrdU and type II cell antigen-positive cells was added minus those cells that had double labeling (so as not to double count the cells). There was a marked increase in proliferation of alveolar epithelial type II cells at 48 and 72 h (BrdU stain) and the number of cells that were positive for the alveolar epithelial type II cell antibody at 48, 72, and 120 h.
For the physiologic studies of alveolar fluid clearance, rats were anesthetized and ventilated. Then, 10 to 12 mL/kg of a 5% albumin solution with 125I-albumin was instilled into the lungs via the trachea. Alveolar liquid clearance was measured over 1 h by the concentration of the labeled and unlabeled alveolar protein as we have done before.1 2 5 6
Results
Alveolar fluid clearance was increased significantly compared with control studies at 48, 72, and 120 h (Table 1) . The peak of alveolar liquid clearance was at 72 h. By 240 h, alveolar fluid clearance had returned to baseline levels. There was an excellent correlation between the increase in alveolar fluid clearance in the KGF-treated rats and the increase in the number of alveolar epithelial type II cells (r = 0.92, p < 0.02).
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Discussion
The results of these studies demonstrate that one dose of KGF induced a sustained increase in the capacity of the alveolar epithelium to transport fluid from the airspaces of the lung for 120 h. Since there was a good correlation between the number of alveolar epithelial type II cells and the rate of alveolar liquid clearance, the primary mechanism for the KGF effect is explained by the increase in the number of alveolar type II cells. Thus, this study establishes that an important mechanism for upregulating alveolar epithelial fluid clearance may be proliferation of alveolar epithelial type II cells. Since alveolar epithelial type II cell proliferation is a well-established morphologic finding in pathologic specimens from patients with ARDS, these findings may have clinical relevance.
In addition, terbutaline upregulated alveolar fluid clearance to an even higher level in the KGF-treated rats. The effect of terbutaline was tested at the peak of the KGF effect, namely 72 h. Thus, the terbutaline data indicate that short-term upregulation can be achieved with ß-adrenergic therapy in recently proliferated alveolar epithelial type II cells.
In summary, the findings of these experimental studies indicate that a sustained increase in alveolar fluid clearance occurs following treatment with one dose of intratracheal KGF in rats. In addition, the study also establishes that an additional short-term upregulation of alveolar fluid clearance can be achieved with ß2-adrenergic stimulation. Since two recent studies reported that ß-adrenergic agonists can increase alveolar liquid clearance in the injured lung,11 12 the findings of this study may have major relevance to the resolution of alveolar edema in patients with clinical acute lung injury.
References
increases alveolar liquid clearance in anesthetized ventilated rats. Am J Physiol 271,L236-L244This article has been cited by other articles:
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  H. Fehrenbach, A. Fehrenbach, T. Pan, M. Kasper, and R.J. Mason Keratinocyte growth factor-induced proliferation of rat airway epithelium is restricted to Clara cells in vivo Eur. Respir. J., November 1, 2002; 20(5): 1185 - 1197. [Abstract] [Full Text] [PDF]
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C. Sartori and M.A. Matthay Alveolar epithelial fluid transport in acute lung injury: new insights Eur. Respir. J., November 1, 2002; 20(5): 1299 - 1313. [Abstract] [Full Text] [PDF]
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