SERUM VASCULAR ENDOTHELIAL GROWTH FACTOR IS ELEVATED IN CYSTIC FIBROSIS AND DECREASES WITH TREATMENT OF ACUTE PULMONARY EXACERBATION

	To the Editor :

McColley and colleagues (1) reported on elevated serum levels of VEGF (VEGF-SL) in patients with cystic fibrosis and asserted that VEGF-SL correlates with airway infections in those patients. Several points should be considered to interpret these data more accurately. Under physiological conditions, virtually no soluble VEGF is present in the blood. The main transporter of VEGF in the blood stream is thrombocytes (2). Platelets contain large amounts of VEGF, and there is a tight correlation between blood platelet counts and VEGF-SL, which is further influenced by platelet size (3). In serum samples, VEGF released from activated platelets during the in vitro clotting process is measured. When citrated plasma samples are analyzed instead (where platelets remain intact), negligible levels of VEGF can be found (4). Thus, the elevated concentrations of VEGF-SL in patients with cystic fibrosis (CF) and pulmonary inflammatory disorders might merely reflect platelet activation and destruction in vitro.

In patients with infection or chronic inflammation, thrombocytosis is frequently present (5). McColley and colleagues state that CF is characterized by profound neutrophilic inflammation and postulated that because neutrophils can release VEGF, elevated VEGF-SL might be a sensitive marker for pulmonary infections in those patients. Sputum cultures of all patients tested were positive for Pseudomonas aeruginosa, and the VEGF-SL levels were found to be maximal at the time of exacerbation, while significantly decreasing after antibiotic therapy.

Not only thrombocytosis, but also platelet hyperreagibility and platelet activation, occur in patients with CF, even in the absence of elevated platelet counts (6). Therefore, increased VEGF-SL might reflect platelet activation and subsequent release of VEGF in vivo and/or in vitro under these circumstances. Furthermore, induction of inflammatory mediator release (thromboxane A2, serotonine) from platelets can be induced by bacterial pathogens, such as P. aeruginosa. Thus, CF, and particularly superinfection with P. aeruginosa, may cause platelet activation. The decline in FEV₁ is likely due to such platelet activation, as platelet-derived mediators cause bronchoconstriction.

Thus, elevated concentrations of VEGF-SL in patients with CF are likely to be caused by thrombocytosis and platelet activation. To further illuminate the findings of McColley and colleagues a more suitable control group should be considered to corroborate their findings; i.e., patients with bronchiectases without P. aeruginosa infection or patients with chronic bronchitis. Nevertheless, the findings of McColley and colleagues might help to elucidate the role of thrombocytosis and platelet activation in CF and the potential role of VEGF blood levels in those patients.

Department of Internal Medicine, University of Innsbruck, Austria

1. McColley SA, Stellmach V, Boas SR, Jain M, Crawford SE. Serum vascular endothelial growth factor is elevated in cystic fibrosis and decreases with treatment of acute pulmonary exacerbation. Am J Respir Crit Care Med 2000; 161: 1877-1880 [Abstract/Free Full Text].

2. Wartiovaara U, Salven P, Mikkola H, Lassila R, Kaukonen J, Joukov V, Orpana A, Ristimaki A, Heikinheimo M, Joensuu H, et al . Peripheral blood platelets express VEGF-C and VEGF which are released during platelet activation. Thromb Haemost 1998; 80: 171-175 [Medline].

3. Gunsilius E, Gasti G. Platelets and VEGF blood levels in cancer patients. Br J Cancer 1999; 81: 185-186 [Medline].

4. Gunsilius E, Petzer A, Stockhammer G, Nussbaumer W, Schumacher P, Clausen J, Gasti G. Thrombocytes are the major source for soluble vascular endothelial growth factor in peripheral blood. Oncology 2000; 58: 169-174 [Medline].

5. Griesshammer M, Bangerter M, Sauer T, Wennauer R, Bergmann L, Heimpel H. Aetiology and clinical significance of thrombocytosis: analysis of 732 patients with an elevated platelet count. J Intern Med 1999; 245: 295-300 [Medline].

6. Stead RJ, Barradas MA, Mikhailidis DP, Jeremy JY, Hodson ME, Batten JC, Dandona P. Platelet hyperaggregability in cystic fibrosis. Prostaglandins Leukot Med 1987; 26: 91-103 [Medline].

	From the Authors:

We thank Drs. Kahlor, Prior, and Gunsilius for their thoughtful comments regarding our study (1). The hypothesis that elevated VEGF in CF sera is related to infection and inflammation in the CF lung is supported by our finding that levels decrease following treatment of acute pulmonary exacerbation. While we speculate that elevations in VEGF are related to the profound neutrophilic inflammation in the CF lung, our data do not allow elucidation of a specific mechanism. Clearly, thrombocytosis or platelet activation that occur during inflammation may be a significant contributing factor. Further studies will be necessary to determine the causes and consequences of elevated serum VEGF in this population, and to validate VEGF as a potential "surrogate marker" for CF pulmonary infection.

Northwestern University Medical School, Chicago, Illinois

1. McColley SA, Stellmach V, Boas SR, Jain M, Crawford SE. Serum vascular endothelial growth factor is elevated in cystic fibrosis and decreases with treatment of acute pulmonary exacerbation. Am J Respir Crit Care Med 2000; 161: 1877-1880 .