Basic Fibroblast Growth Factor Levels in the Vitreous of Patients With Proliferative Diabetic Arunan Sivalingam, MD; John Kenney, MS; Gary C. William E. Benson, MD; Larry Donoso, MD, PhD \s=b\ A two-site enzyme-linked immunosorbent assay was used to quantitate levels of basic fibroblast growth factor in the vitreous from 36 patients undergoing vitrectomy for a variety of retinal conditions, including proliferative diabetic retinopathy, macular pucker, and retinal detachment with and without proliferative Basic fibroblast vitreoretinopathy. growth factor levels ranged from undetectable to 52 ng/mL. In patients with proliferative diabetic retinopathy, basic fibroblast growth factor levels were greater than or equal to 30 ng/mL in 8 of 17 specimens. Of the 8 patients with elevated basic fibroblast growth factor levels, 6 had evidence of active proliferative disease (ie, neovascularization of the disc or iris), whereas in the patients who had undetectable levels only 2 of 9 had evidence of neovascularization of disc and none had neovascularization of the iris. In the rhegmatogenous retinal detachment group, 2 of 10 eyes had elevated basic fibroblast growth factor levels, while none in the macular pucker group had elevated levels. Our study documents increased levels of basic fibroblast growth factor in vitreous specimens from patients with proliferative diabetic retinopathy, particularly those with active proliferative retinopathy. The role of basic fibroblast growth factor in the pathogenesis of various retinal disease entities is discussed.

(Arch Ophthalmol. 1990;108:869-872) Accepted for publication January 18, 1990. From the Retina Service, Wills Eye Hospital and Thomas Jefferson University, Philadelphia, Pa (Drs Sivalingam, Brown, Benson, and Donoso), and Syntex Research, Palo Alto, Calif (Mr Kenney). Dr Donoso is the Thomas Duane Professor of Ophthalmology, Jefferson Medical College, Thomas Jefferson University. Reprint requests to Wills Eye Hospital, Philadelphia, PA 19107 (Dr Donoso).

Retinopathy

Brown, MD;

rPhe

identification

of

angiogenic

agents is of importance

in many pathological disease processes affect¬ ing the eye, such as proliferative dia¬ betic retinopathy (PDR), retinopathy of prematurity, sickle cell retinopathy, and neovascular glaucoma. In 1948, Michaelson1 first proposed that a chemical factor in the retina controls the development of the retinal vasculature and suggested its involvement in retinal vascular disorders. Ashton et al,2 in a report on retinopathy of pre¬ maturity, suggested that retinal isch¬ emia or hypoxia provided the stimulus for release of the angiogenic factor. Subsequent investigations have pro¬ vided many observations that support these hypotheses. Extracts from mam¬ malian retinas have been shown to induce basement membrane degrada¬ tion, endothelial cell migration and

proliferation, and neovascularization.3 In animal models, angiogenesis can be induced by ischemia brought about by experimental retinal vein occlusion.4 Vitreous and aqueous aspirates from these animals are mitogenic for human endothelial cells, whereas those from

nonoccluded animal eyes are not.5 Fur¬ thermore, endothelial cell mitogenic activity has been found in the vitreous and aqueous removed from human eyes with neovascular glaucoma or

PDR.5

Several different lines of investiga¬ tion have implicated basic fibroblast growth factor (ßFGF), a potent growth and differentiation factor for mesoderm- and neuroectoderm-derived cells, as a principal angiogenic factor in the eye. Courty et al6 first isolated three growth factor activities from the bovine retina, which were designated as eye-derived growth fac-

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I, II, and III. Eye-derived growth factors I and II were later identified as being identical to ßFGF and acidic fibroblast growth factor (aFGF), re¬ spectively.7"12 The FGFs, which have a 55% aminoacid sequence homology, bind to the same receptor and are highly conserved across species.13 However, ßFGF is 30- to 100-fold more potent than acidic FGF.9'4 In retinal extracts, ßFGF is the principal eye-derived growth factor both in rela¬ tive potency and concentration.10,14 In vitro, ßFGF stimulates the prolifera¬ tion of corneal endothelial cells at a concentration as low as 5 pg/mL.10 This concentration is 20- to 60-fold lower than the concentration required to trigger cell proliferation by transform¬ ing growth factor ß (TGFß), epidermal tors

growth factor, or platelet-derived growth factor.15 As little as 0.3 ng/mL induces massive capillary formation in

the rabbit cornea.16 Despite the presence of ßFGF in the eye and other tissues, the rate of new vessel formation in these tissues is normally very low. The basis of vessel formation in the normal eye can be accounted for by mechanisms that reg¬ ulate the release of ßFGF into the surrounding milieu. Basic FGF lacks the signal peptide typical of secretory proteins and as a consequence is only cell associated.1718 Also, ßFGF's affini¬ ty for heparin, a constituent of extra¬ cellular basement membrane, limits its

availability to adjacent cells.19"21 Several mechanisms of ßFGF

re¬

lease have been described that may occur during retinal ischemia. Basic FGF can be released following the exposure of endothelial cells to injuri¬ ous agents.18 Additionally, FGF bound to heparin in the extracellular base-

Table 1.—Vitreous

No. of Patients by Level of (SFGF Patient

Group PDR

Macular

pucker

RD Miscellaneous

ng/mL

Undetectable

8 0 2

9 5

t

3

*/?FGF indicates basic fibroblast growth factor; PDR, proliferative diabetic retinopathy; and RD, reti¬ nal detachment.

/ÏFGF

Active Proliferative

Inactive Proliferative

Level

Retinopathy

Retinopathy

>30 ng/mL* * Undetectable

6 2

2 7

*P=

ment membrane can be released fol¬ lowing exposure to heparitinase and

plasmin.19"21 Thus,

release of ßFGF from the cell or basement membrane may provide the stimulus for induction of neovascularization in pathological conditions of the eye. If the release of ßFGF provides an important stimulus for neovasculariza¬ tion in eye disorders, the presence of ßFGF should theoretically be detected in vitreous fluids. Bioassays for ßFGF are inherently nonspecific since they can detect other growth factors. circumvent these problems, we uti¬ lized ßFGF-specific monoclonal anti¬ bodies (mAbs) in an immunoassay to detect and quantitate ßFGF in vitre¬ ous fluid from patients with various proliferative diseases of the retina. MATERIALS AND METHODS

Specimens Thirty-six vitreous samples were ob¬ tained. The standard three-port vitrectomy technique was used. A 5-mL syringe was used to aspirate a minimum of 0.4 mL of undiluted vitreous fluid through the vitrec¬ tomy probe after the infusion port was placed without turning the fluid on. After the specimen was obtained, it was frozen at

20°C until the assay was carried out. These 36 specimens were divided into four groups (Table 1) based on the patients' clinical diagnosis and included: PDR (17 patients), macular pucker (5 patients), rhegmatogenous retinal detachment (10 patients), isch¬ emie retinal vein occlusion (1 patient), cystoid macular edema (1 patient), large cell lymphoma (1 patient), and vitreous hemor¬ rhage resulting after repair of rhegmatogenous retinal detachment (1 patient).

Immunoassay for ßFGF Samples were diluted 1:10 and assayed (in duplicate) by two-site enzyme-linked immunosorbent assay using two mAbs spe¬ cific for ßFGF. The mAbs and enzymelinked immunosorbent assay

No. of Patients

8

were

devel¬

oped as previously described.22'23 The mAbs used in this assay, designated HFG8-H32 and HFG8-H37, bind recombinant human ßFGF and pituitary- and kidney-derived bovine ßFGF. They do not bind non-ßFGF members of the FGF gene family,13 such as bovine acidic FGF and human interleukin 1 alpha and interleukin 1 beta. The concentra¬ tion of ßFGF in each sample was calculated

.044.

from the standard

curve

of human recombi¬

ßFGF using Immunofit Software (Beckman Instruments, Palo Alto, Calif) and then corrected for sample dilution. The minimum detectable dose24 of the standard was 2.4 ng/mL. Measurement of human recombinant FGF was not affected by the presence of human plasma or heparin. nant

RESULTS

Vitreous levels of ßFGF from 36 patients ranged from undetectable to 52 ng/mL. All patients with detectable

levels had a range from 30 to 52 The numbers of patients, by group, with ßFGF levels greater than or equal to 30 ng/mL are summarized in Table 1. The greatest number of patients with elevated ßFGF levels were in the PDR group (17 patients). When ßFGF levels from patients from this group were compared with ßFGF levels from all other groups, the data

ng/mL.

were

statistically

significant

at

.046 (Fisher's Exact Test). Fish¬ er's Exact Test was calculated for onetailed interpretation. Virtectomy specimens from patients who underwent vitrectomy for PDR were further subdivided into speci¬ mens from those patients who had surgery for persistent vitreous hemor¬ rhage (nine patients) and those who underwent vitrectomy for traction ret¬ inal detachment (eight patients). Ele¬ vated levels of ßFGF were found in eight of nine patients who underwent vitrectomy for persistent vitreous hemorrhage. None of the traction reti¬ nal detachment group had elevated levels of ßFGF ( .005). The eight patients with elevated ßFGF levels who had undergone vitrectomy for persistent vitreous hemorrhage had the vitreous hemorrhage from 1 to 5 months preoperatively. The one pa¬ tient with vitreous hemorrhage and an undetectable level of ßFGF had under¬ gone vitrectomy for persistent blood of 3 months' duration. In addition, six of the eight patients in the traction reti¬ nal detachment group also had a com¬ ponent of vitreous hemorrhage. In two of the eight patients with traction reti¬ nal detachment, the vitreous hemor=

=

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was sufficiently severe to pre¬ preoperative fundus view. Among the eight diabetic patients with elevated levels of vitreous ßFGF, seven had undergone panretinal photocoagulation (PRP) preoperatively. Five of the seven patients had under¬

vent

Retinopathy

,-,

>30

rhage

Table 2.—Elevated Basic Fibroblast Growth Factor (/3FGF) Levels in Patients With Active Proliferative

/ÎFGF Levels*

a

gone PRP 1 to 2 years before vitrec¬ two of seven had undergone PRP 4 to 5 years before vitrectomy. All of these seven patients underwent supplemental PRP preoperatively within 1 year of their surgery. The remaining patient with elevated ßFGF level did not undergo any preoperative PRP but underwent endophotocoagulation during surgery. Within the group of eight diabetic

tomy and

patients who demonstrated elevated vitreous levels of ßFGF, five had clini¬ cally documented active neovasculari¬ zation of the disc (NVD), either just before their vitreous hemorrhage or intraoperatively. One patient had neo¬ vascularization of the iris (NVI). Thus, six of the eight patients with elevated ßFGF had active ocular neovasculari¬ zation documented clinically (Table 2). Among the diabetic patients who had undetectable vitreous ßFGF lev¬ els, five of nine patients underwent preoperative PRP and one patient un¬ derwent preoperative peripheral cryoablation. Of the five patients who underwent preoperative PRP, one un¬ derwent PRP 8 months preoperative¬ ly. The remaining four patients under¬ went PRP 4 to 8 years preoperatively. Only one of these four patients under¬ went a supplemental PRP within 1 year before the

other three

vitrectomy, and patients underwent

the

no

supplemental treatment after their ini¬ tial PRP. Only two of the nine patients with undetectable vitreous ßFGF lev¬

els had active NVD documented pre¬ operatively or intraoperatively. Six patients had severe fibrous prolifera¬ tion leading to traction retinal detach¬ ment but did not have active NVD or NVI. The remaining one patient who had undetectable ßFGF levels had un¬ dergone vitrectomy for vitreous hem¬ orrhage but again had no evidence of NVD or NVI. Thus, only two of nine diabetic patients with undetectable vitreous ßFGF levels had active prolif¬ erative retinopathy (Table 2). When the presence of active NVD or NVI in the diabetic group with elevated vitre¬ ous ßFGF is compared with the group with undetectable ßFGF levels, the presence of active proliferative disease in the former is statistically significant at =.044 (Fisher's Exact Test, onetailed interpretation). Basic FGF was also detected in two of four patients with severe prolifera-

tive vitreoretinopathy (stage D, per the Retina Society terminology committee2")- The other six patients in the retinal detachment group underwent vitrectomy for a number of conditions, including retinal detachment resulting from the following: macular hole (one patient), giant tear (one patient), and expulsive choroidal hemorrhage (one patient), as well as rhegmatogenous retinal detachment with stage Cl PVR (three patients). All of these latter six patients in the retinal detachment group had undetectable levels of

ßFGF.

In the miscellaneous group, one pa¬ tient who underwent vitrectomy for an ischemie central retinal vein obstruc¬ tion demonstrated an elevated level of ßFGF. The levels were normal in the other three patients in this group. Reasons for vitrectomy in these latter three included cystoid macular edema in one patient, large cell lymphoma in one, and vitreous hemorrhage of 5 months' duration following repair of retinal detachment in the remaining

patient.

COMMENT

Basic FGF may play a role in the pathogenesis of proliferative diseases of the retina, including diabetes, sickle cell retinopathy, and retinopathy of prematurity. In our study, we have used a sensitive and highly specific mAb-based assay to detect ßFGF in vitreous samples. This assay has the advantage that mAbs do not crossreact with other growth factors that may be detected in bioassays or in polyclonal antibody-based immunoassays. It is most likely that ßFGF detected in the vitreous is derived from the retina and not from plasma or other infiltrating blood components. Glaser et al26 have demonstrated that FGF activity can be extracted from the reti¬ na when all blood is removed prior to extraction. The in vivo half-life of ßFGF in the blood is on the order of seconds (J. A. Abraham, PhD, oral communication, July 15, 1988). In addition, ßFGF is not detected in hu¬ man plasma using the immunoassay we

employed (J.K., unpublished data,

June 1989). In our study, we found elevated levels of ßFGF in some patients with PDR. There has been one previous report of increased ßFGF levels in patients with PDR,27 although the va¬ lidity of the assay has been ques¬ tioned.28 We did not detect elevated levels of ßFGF in all the patients with PDR studied, although ßFGF level was generally consistently elevated in

those

patients with persistent vitreous hemorrhage compared with those with

traction retinal detachment. It could be postulated that vitreous hemor¬ rhage causes an influx of macrophages into the vitreous cavity. Macrophages have been known to have the capabili¬ ty to produce ßFGF.29 The possibility exists that we are simply detecting the ßFGF present in the macrophages. Nevertheless, we doubt that the in¬ creased levels of the ßFGF in the vitreous are secondary to macro¬ phages, because most of the patients in the traction retinal detachment group with undetectable ßFGF levels also had some component of vitreous hem¬ orrhage. In fact, at least two of the patients in the diabetic-traction de¬ tachment group had vitreous hemor¬ rhage such that it precluded the view of fundus preoperatively. Further¬ more, the patient who underwent vi¬ trectomy for vitreous hemorrhage of 5 months' duration after repair of retinal detachment also had an undetectable level of ßFGF. If macrophages pro¬ duced significant amounts of ßFGF, we should have detected ßFGF in the above patients with significant vitre¬ ous hemorrhage in the traction retinal detachment and the patient with vitre¬ ous hemorrhage after the repair of retinal detachment. Since the detec¬ tion limit of the immunoassay is not as low as concentrations of ßFGF known to have a biological effect, a role for ßFGF in the traction retinal detach¬ ment group cannot be excluded. The presence of active proliferative disease, as characterized by NVD or NVI, seems to correlate well with the elevated vitreous ßFGF group (75% of the patients demonstrated prolifera¬ tive disease). In the group with unde¬ tectable ßFGF, only 22% of the pa¬ tients had active proliferative retinopathy. We could possibly postu¬ late that ßFGF is more likely to be released into the vitreous cavity when there is the presence of active prolifer¬ ative retinopathy. This observation supports the hypothesis that ßFGF may play an important role in the pathogenesis of PDR. We also found higher levels of ßFGF in vitrectomy specimens from two of four patients with stage D PVR. The number of patients in this group is small, and evaluation of the role of ßFGF in this clinical disorder requires further study. By using immunohistochemical tech¬ niques, FGF has been shown to bind to the vascular endothelial basement

membrane, rin sulfate,

more a

specifically

to

hepa¬

basement membrane could be correlat¬ ed to certain clinical observations en¬ countered in patients with PDR. It has been observed that in phakic patients with PDR who undergo vitrectomy, the incidence of rubeosis is higher when lensectomy is also performed.31 This could be accounted for by the lens acting as a barrier or ischemia result¬ ing from an oxygen steal phenomenon into the posterior chamber.32 Experi¬ mental evidence supports the barrier theory, since lens capsule is a base¬ ment membrane containing heparin

sulfate.33 Therefore,

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postulate

cases.

component of basement

membrane.30 The binding of FGF to

one can

that the reason for the decreased inci¬ dence of rubeosis in phakic eyes, com¬ pared with aphakic eyes, is that the heparin sulfate component of lens basement membrane binds to FGF, acting as a sponge or sink preventing its flow into the anterior chamber. In addition, the accumulation of growth factor within the lens capsule may account for the observation that cer¬ tain phakic patients with severe PDR develop retrolenticular neovascular¬ ization. Insulinlike growth factor I level has been reported to be elevated in the vitreous and serum in patients with PDR.34'35 In another study, we did not find insulinlike growth factor levels to be significantly different between PDR vs macular pucker and retinal detachment groups (unpublished data). The relative potency of insulinlike growth factor is not as great as ßFGF, which suggests that insulinlike growth factor may not be as an important angiogenic agent as ßFGF in patients with PDR. Glaser and associates26 have proposed that TGFß is important in angiogenesis. Although in vivo TGFß has been shown to stimulate neovascu¬ larization, in vitro it inhibits FGFinduced vascular endothelial cell prolif¬ eration.36 Recently, TGFß has been shown to have a role in fibrosis. Con¬ nor and associates37 also have suggest¬ ed a role for TGFß in moderate and severe PVR cases. The levels of TGFß in those patients are three times the levels found in patients with uncompli¬ cated retinal detachment.37 Collective¬ ly, these results suggest that FGF may have important angiogenesis func¬ tion in patients with PDR with active proliferative retinopathy such as NVD or NVI, whereas TGFß may be impor¬ tant in the resolution stage of neovas¬ cularization, leading to fibrosis and traction retinal detachment. Further research is needed to further clarify the roles of TGFß and ßFGF in these This work

was

supported in part by

the Retina

Service of Wills Eye Hospital, Philadelphia, Pa; the Crippled Childrens Vitreo Retinal Research Foundation (David Meyer, MD, director); the Pennsylvania Lions Sight Conservation and Eye Research Foundation Ine; and grants EY 5095

and BRSG 5510 from the National Institutes of Health, Bethesda, Md. Dr Donoso is the recipient of a Manpower Award from Research to Prevent Blindness Ine, New York, NY. Human recombinant ßFGF was a kind gift of

California Biotechnology, Mountain View, Calif. We thank J. Augsburger for help with statisti¬ cal analysis.

References 1. Michaelson IC. The mode of development of the vascular system of the retina, with some observations on its significance for certain retinal disease. Trans Ophthalmol Soc UK. 1948;68:137-180. 2. Ashton N, Ward B, Serpell G. Effect of oxygen on developing retinal vessels with particular reference to the problems of retrolental fibroplasia. Br J Ophthalmol. 1954;38:397-432. 3. Sebag J, McMeel JW. Diabetic retinopathy: pathogenesis and the role of retina-derived growth factor in angiogenesis. Surv Ophthalmol. 1986; 30:377-384. 4. Virdi PS, Hayreh SS. Ocular neovascularization with retinal vascular occlusion, I: association with experimental retinal vein occlusion. Arch

Ophthalmol. 1982;100:331-341.

5. Gu XQ, Fry GL, Lata GF, et al. Ocular neovacularization: tissue culture studies. Arch Ophthal-

mol. 1985;103:111-117. 6. Courty J, Loret C, Moenner M, et al. Bovine retina contains three growth factor activities with different affinity to heparin: eye derived growth factor I, II, III. Biochimie. 1985;67:265-269. 7. D'Amore PA, Klagsbrun M. Endothelial cell mitogens derived from retina and hypothalamus: biochemical and biological similarities. J Cell Biol.

1984;99:1544-1549.

8. Schreiber AB, Kenney J, Kowalaski J, et al. A unique family of endothelial cell polypeptide mitogens: the antigenic and receptor cross-reactivity of bovine endothelial cell growth factor, brain-derived acidic fibroblast growth factor, and eye-derived growth factor-II. J Cell Biol. 1985;101:1623\x=req-\

1626. 9. Bohlen P, Esch F, Baird A, et al. Acidic fibroblast growth factor from bovine brain: amino terminal sequence and comparison to basic fibroblast growth factor. EMBO J. 1985;4:1951-1956. 10. Baird A, Esch F, Gospodarowicz D, et al. Retina and eye-derived endothelial cell growth factors: partial molecular characterization and identity with acidic and basic fibroblast growth factors.

Biochemistry. 1985;24:7855-7860. 11. Courty J, Chevallier B, Moenner M,

et al. Evidence for FGF-like growth factor in adult bovine retina: analogies with EDGF I. Biochem Biophys Res Commun. 1986;136:102-108. 12. Mascarelli F, Raulais D, Counis MR, Courtois Y. Characterization of acidic and basic fibroblast growth factors in brain, retina and vitreous chick embryo. Biochem Biophys Res Commun.

1987;146:478-486.

13. Gospodarowicz D, Ferrara N, Schweigerer L. Structural characterization and biological func-

growth factor. Endocr Rev. 1987;8:95-114. 14. Albert P, Boilly B, Courty J, et al. Stimulation in cell culture of mesenchymal cells of newt limb blastemas by EDGF I or II (basic or acidic FGF). Cell Differ. 1987;21:63-68. 15. Gospodarowicz D, Massoglia S, Cheng J, et al. Isolation of pituitary fibroblast growth factor by fast protein liquid chromatography: partial chemical and biological characterization. J Cell Physiol. 1985;122:323-332. 16. Gospodarowicz D, Bialecki H, Thakral TK. The angiogenic activity of the fibroblast and epidermal growth factor. Exp Eye Res. 1979;28:501-514. 17. Abraham JA, Whang A, Tumolo J, et al. Human basic fibroblast growth factor: nucleotide sequence and genomic organization. EMBO J. tions of fibroblast

1986;5:2523-2528.

18. Gajdusek CM, Carbon S. Injury-induced release of basic fibroblast growth factor from bovine aortic endothelium. J Cell Physiol. 1989;139:570\x=req-\ 579. 19. Baird A, Ling N. Fibroblast growth factors are present in the extracellular matrix produced by endothelial cells in vitro: implications for a role of heparinase-like enzymes in the neovascular response. Biochem Biophys Res Commun. 1987; 142:428-435. 20. Folkman J, Klagsbrun M, Sasse J. A heparin-binding angiogenic protein, basic fibroblast growth factor, is stored within basement membrane. Am J Pathol. 1988;130:393-400. 21. Bashkin P, Doctrow S, Klagbrun M, et al. Basic fibroblast growth factor binds to subendothelial extracellular matrix and is released by hepari-

tinase and

heparin-like molecules. Biochemistry.

1989;28:1737-1743. 22. Massoglia SL, Kenney JS, Gospodarowicz

D. Characterization of murine monoclonal antibodies directed against basic fibroblast growth factor. J Cell Physiol. 1987;132:531-537. 23. Kenney JS, Masada MP, Allison AC. Development of quantitative two-site ELISAs for soluble proteins. In: Zola H, ed. Laboratory Methods in Immunology, I. Boca Raton, Fla: CRC Press Inc;

1989;20.

24. Rodbard

D, Munson PJ, DeLean A. Im-

proved curve-fitting, parallelism testing, characterization of sensitivity and specificity, validation, and optimization for radioligand assays: radioimmunoassays and related procedures in medicine. IAEA. 1978;1:469-514. 25. Retina society terminology committee: the classification of retinal detachment with prolifera-

Downloaded From: http://archopht.jamanetwork.com/ by a University of Manitoba User on 06/06/2015

tive retinal detachment. Ophthalmology. 1981; 90:121-125. 26. Glaser BM, D'Amore PA, Michels RG, et al. Demonstration of vasoproliferative activity from ocular tissue. Ophthalmology. 1980;87:440-446. 27. Baird A, Culler F, Jones KL, et al. Angiogenic factor in human ocular fluid. Lancet.

1985;2:563.

28. Gauthier T, Maftouh M, Picard C. Rapid enzymatic degradation of (125I)(tyr 10) by serum in

vitro and involvement in the determination of circulating FGF by RIA. Biochem Biophys Res Commun.

1987;145:775-781.

29. Baird A, Mormede P, Bohlen P. Immunoreactive fibroblast growth factor in cells of peritoneal exudate suggest its identity with macrophage-derived growth factor. Biochem Biophys Res Commun.

1985;126:358-364.

Lutty G, Hjelmeland L, et al. Basic fibroblast growth factor stores in proliferadiabetic tive retinopathy. In: Program and abstracts of the annual meeting of the Association for Research in Vision and Opthalmology; April 30\x=req-\ May 5,1989; Sarasota, Fla. Abstract 138. 31 Blankenship G, Cortez R, Machemer R. The lens and pars plana vitrectomy for diabetic retinopathy complications. Arch Ophthalmol. 1979; 97:1263-1267. 32. Stefansson E, Landers MB III, Wolbarsht ML. Increased retinal oxygen supply following pan-retinal photocoagulation and vitrectomy and lensectomy. Trans Am Ophthalmol Soc. 1981; 79:307-331. 33. Dische Z, Zelmania G, Rothschild C. The hexosaminohexuronide of the bovine lens capsule. Arch Biochem Biophys. 1967;21:685-694. 34. Merimee T, Zapf J, Froesch E. Insulin-like growth factors studies in diabetics with and without retinopathy. N Engl J Med. 1983;309:527-530. 35. Russell M, Fitzgerald C, Merimee J. Insulin like growth factors in vitreous studies in control and diabetic subjects with neovascularization. Diabeties. 1986;35:416-420. 36. Lansing M, Jerdan J, Dugan A, et al. The bifunctional role of transforming growth factors beta-1 and beta-2 in neovascularization in the mature animal. In: Program and abstracts ofthe annual meeting of the Association for Research in Vision and Opthalmology; April 30-May 5,1989; Sarasota, Fla. Abstract 392. 37. Connor T, Roberts A, Sporn M, et al. Correlation of fibrosis and transforming growth factor\x=req-\ beta type 2 levels in the eye. J Clin Invest. 30. Hanneken A,

1989;83:1661-1666.

Basic fibroblast growth factor levels in the vitreous of patients with proliferative diabetic retinopathy.

A two-site enzyme-linked immunosorbent assay was used to quantitate levels of basic fibroblast growth factor in the vitreous from 36 patients undergoi...
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