A non-invasive method to produce pressure ulcers of varying severity in a spinal cord-injured rat model.

STUDY DESIGN: Experimental study. OBJECTIVES: The objective of this study was to establish a non-invasive model to produce pressure ulcers of varying severity in animals with spinal cord injury (SCI). SETTING: The study was conducted at the Johns Hopkins Hospital in Baltimore, Maryland, USA. METHODS: A mid-thoracic (T7-T9) left hemisection was performed on Sprague-Dawley rats. At 7 days post SCI, rats received varying degrees of pressure on the left posterior thigh region. Laser Doppler Flowmetry was used to record blood flow. Animals were killed 12 days after SCI. A cardiac puncture was performed for blood chemistry, and full-thickness tissue was harvested for histology. RESULTS: Doppler blood flow after SCI prior to pressure application was 237.808±16.175 PFUs at day 7. Following pressure application, there was a statistically significant decrease in blood flow in all pressure-applied groups in comparison with controls with a mean perfusion of 118.361±18.223 (P<0.001). White blood cell counts and creatine kinase for each group were statistically significant from the control group (P=0.0107 and P=0.0028, respectively). CONCLUSIONS: We have created a novel animal model of pressure ulcer formation in the setting of a SCI. Histological analysis revealed different stages of injury corresponding to the amount of pressure the animals were exposed to with decreased blood flow immediately after the insult along with a subsequent marked increase in blood flow the next day, conducive to an ischemia-reperfusion injury (IRI) and a possible inflammatory response following tissue injury. Following ischemia and hypoxia secondary to microcirculation impairment, free radicals generate lipid peroxidation, leading to ischemic tissue damage. Future studies should be aimed at measuring free radicals during this period of increased blood flow, following tissue ischemia.

Ischemia reperfusion-facilitated sinusoidal endothelial cell injury in liver transplantation and the resulting impact of extravasated platelet aggregation.

BACKGROUND: The exact sequence of events leading to ultimate hepatocellular damage following ischemia/reperfusion (I/R) is incompletely understood. In this article, we review a mechanism of organ dysfunction after hepatic I/R or immunosuppressive treatment, in addition to the potential of liver sinusoidal endothelial cell (LSEC) protection and antiplatelet treatment for the suppression of hepatocellular damage. METHODS: A review of the literature, utilizing PubMed-NCBI, was used to provide information on the components necessary for the development of hepatocellular damage following I/R. RESULTS: It is well-established that LSECs damage following hepatic I/R or immunosuppressive treatment followed by extravasated platelet aggregation (EPA) is the root cause of organ dysfunction in liver transplantation. We have classified three phases, from LSECs damage to organ dysfunction, utilizing the predicted pathogenic mechanism of sinusoidal obstruction syndrome. The first phase is detachment of LSECs and sinusoidal wall destruction after LSECs injury by hepatic I/R or immunosuppressive treatment. The second phase is EPA, accomplished by sinusoidal wall destruction. The various growth factors, including thromboxane A2, serotonin, transforming growth factor-beta and plasminogen activator inhibitor-1, released by EPA in the Disse's space of zone three, induce portal hypertension and the progression of hepatic fibrosis. The third phase is organ dysfunction following portal hypertension, hepatic fibrosis, and suppressed liver regeneration through various growth factors secreted by EPA. CONCLUSION: We suggest that EPA in the space of Disse, initiated by LSECs damage due to hepatic I/R or immunosuppressive treatment, and activated platelets may primarily contribute to liver damage in liver transplantation. Endothelial protective therapy or antiplatelet treatment may be useful in the treatment of hepatic I/R following EPA.

Combination of HIF-1α gene transfection and HIF-1-activated bone marrow-derived angiogenic cell infusion improves burn wound healing in aged mice.

Impaired burn wound healing in the elderly represents a major clinical problem. Hypoxia-inducible factor-1 (HIF-1) is a transcriptional activator that orchestrates the cellular response to hypoxia. Its actions in dermal wounds promote angiogenesis and improve healing. In a murine burn wound model, aged mice had impaired wound healing associated with reduced levels of HIF-1. When gene therapy with HIF-1 alone did not correct these deficits, we explored the potential benefit of HIF-1 gene therapy combined with the intravenous infusion of bone marrow-derived angiogenic cells (BMDACs) cultured with dimethyloxalylglycine (DMOG). DMOG is known to reduce oxidative degradation of HIF-1. The mice treated with a plasmid DNA construct expressing a stabilized mutant form of HIF-1α (CA5-HIF-1α)+BMDACs had more rapid wound closure. By day 17, there were more mice with completely closed wounds in the treated group (χ(2), P=0.05). The dermal blood flow measured by laser Doppler showed significantly increased wound perfusion on day 11. Homing of BMDACs to the burn wound was dramatically enhanced by CA5-HIF-1α gene therapy. HIF-1α mRNA expression in the burn wound was increased after transfection with CA5-HIF-1α plasmid. Our findings offer insight into the pathophysiology of burns in the elderly and point to potential targets for developing new therapeutic strategies.

Current Insights into the role of HIF-1 in cutaneous wound healing.

Hypoxia Inducible Factor-1 (HIF-1) is considered the major coordinator of the cellular adaptive response to hypoxia. Over recent years, its activity in the context of wound healing has been the object of increasing investigation. On the molecular level, HIF-1 transcriptional target products have been shown to regulate the process of endothelial cell survival, migration and proliferation (VEGF, ANGPT-1, ANGPT-2, ANGPT-4, FGF-2, PlGF, PDGF-B, RGC-32), vascular smooth muscle cell migration and proliferation (FGF-2, EGF, PDGF, thrombospondin) and mobilization of Circulating Angiogenic Cells to the periphery (SFD-1/CXCR4). Studies on the effect of HIF-1 on the expression and activity of extracellular cell matrix modifying enzymes, such as MMPs and prolidase, have been conducted in the context of tumor angiogenesis and metastasis, and have resulted in controversial findings. A growing body of evidence suggests that HIF-1 also affects reepithelialization of the wound bed, through increasing keratinocyte migration, but decreasing their proliferation. Diminished HIF-1 levels and activity have been documented in conditions of impaired wound healing, such as wound healing in aged and in diabetic mice. The increasing number of studies on the role of HIF-1 in wound healing, apart from answering certain questions, has also raised an equal number, if not more. Clarifying the topics that still remain unclear could introduce a new era of HIF-1 targeted management of a wide range of problematic wounds.

Electroporative transfection with KGF-1 DNA improves wound healing in a diabetic mouse model.

We recently demonstrated that electroporation enhances transfection in a mouse wound-healing model. Keratinocyte growth factor (KGF) is an inducer of epithelial cell proliferation and differentiation and has been shown to be under expressed in the wounds of diabetic individuals. We hypothesized that KGF delivered into an excisional wound via naked DNA injection with subsequent electroporation would be a novel and potentially effective method to enhance wound closure in a diabetic mouse model. ELISA assays confirmed production of KGF protein in cultured mouse cells and RT-PCR assays confirmed KGF mRNA in skin samples taken from mice. In all, 32 genetically diabetic mice were given two identical excisional wounds of their dorsum and split into two groups with one group receiving KGF DNA injection and electroporation with the other group receiving no treatment. Over 90% of wounds healed in the presence of KGF and electroporation versus 40% in the untreated group by day 12. Histological analysis of the wounds demonstrated that untreated wounds contained microulcers with thin or incomplete epithelium with unresolved inflammation as compared to treated wounds where intact and mature epithelium was observed. Taken together these findings suggest that a single injection of KGF DNA encoded on a plasmid coupled with electroporation improves and accelerates wound closure in a delayed wound-healing model.

Synthetic retinoid CD437 induces apoptosis of esophageal squamous HET-1A cells through the caspase-3-dependent pathway.

6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN/CD437) is a novel retinoid that has shown to be a potent inducer of apoptosis in cancer cells. We investigated the apoptosis-inducing activity of CD437 and its mechanism of action in the human esophageal squamous epithelial cell line (HET-1A). CD437 decreased HET-1A cell viability in a time and dose dependent manner. CD437 was found to induce DNA fragmentation. Apoptosis was accompanied by markedly increased activity of caspase-3 as well expression of caspase-3 and -8 and APRP fragmentation. The CD437-mediated activation of caspase-3 was inhibited by Z-DEVD-FMK These data indicate that CD437-induced apoptosis in HET-1A cells may be mediated through the caspase-3 dependent pathway. In addition, apoptosis was also accompanied by increased expression of Bad protein and down-regulation of Bcl-2 expression. Phosphorylation of Jun occurred following CD437 exposure indicating that Jun kinase (JNK) activity was strongly induced by CD437. Understanding these apoptotic pathways of esophageal epithelial cells may allow therapeutic induction of cell death in malignant orpremalignant lesions of the esophagus by agents such as CD437.

Evidence of androgen receptor expression in squamous and adenocarcinoma of the esophagus.

Androgen receptors (AR) are known to stimulate cellular proliferation in certain tumors. We have assessed the androgen receptor status of esophageal carcinoma in surgically resected specimens as well as in established human esophageal carcinoma cells lines. In these initial studies we sought to characterize the frequency of expression of androgen receptors in squamous versus adenocarcinoma and in male versus female patients, and to assess the possible influence of AR expression on survivaL We analyzed androgen receptor expression utilizing immunohistochemistry in adenocarcinoma and squamous cell carcinoma of the esophagus in surgical specimens from 25 patients treated at Johns Hopkins Bayview Medical Center. Tumors in 7 of 21 males (33%) and 1 of 4 females (25%) showed positive androgen receptor staining with the monoclonal body antibody AR 441. There was no suggestion of a difference in expression of AR between males and females. Five of 11 adenocarcinomas (45%) and 3 of 14 squamous carcinomas were positive. Survival was similar in AR+ and AR- patients. Studies with established tissue culture cell lines showed AR expression by RT-PCR, with stronger expression of AR in adenocarcinoma lines than in squamous carcinoma lines. The presence of AR in human esophageal cancer is an impetus for further studies to assess anti-androgen therapy for treatment and or prevention of these tumors.

Parathyroidectomy promotes wound healing and prolongs survival in patients with calciphylaxis from secondary hyperparathyroidism.

BACKGROUND: Calciphylaxis is a rare but life-threatening condition occasionally affecting patients with secondary hyperparathyroidism. Parathyroidectomy has been advocated as the only potentially curative intervention. METHODS: Between January 1989 and May 2000, 13 patients with pathologic/clinical criteria of calciphylaxis were treated at our institution. Of these 13 patients, 7 were managed with medical therapy alone, and 6 were referred for parathyroidectomy. The medical records were reviewed, and patients/relatives were interviewed. RESULTS: All patients had cutaneous wounds requiring local debridement predominantly located on the lower extremities or abdominal wall. Six patients underwent subtotal (3.5 gland) parathyroidectomy without morbidity. All 6 had significant reductions in parathyroid hormone levels after surgery (mean decrease, 94% +/- 0%), and all reported resolution of pain and healing of cutaneous wounds. Of the remaining 7 patients who had medical management alone, 5 eventually died of complications related to calciphylaxis. In comparing the 2 groups, patients who underwent parathyroidectomy had a significantly longer median survival than those who did not have surgery (36 vs 3 months, P =.021). CONCLUSIONS: Calciphylaxis frequently causes gangrene, sepsis, and eventual death. Parathyroidectomy can be performed with minimal morbidity and is associated with resolution of pain, wound healing, and a significantly longer median survival. Therefore, patients with secondary hyperparathyroidism and signs/symptoms of calciphylaxis should be referred promptly for consideration of parathyroidectomy.

Acidic fibroblast growth factor overexpression partially protects 3T3 fibroblasts from apoptosis induced by synthetic retinoid CD437.

Retinoids are proapoptotic compounds with therapeutic potential for treating cancer. We evaluated the apoptotic effect of the novel retinoid CD437, and particularly its relationship to Akt and acidic fibroblast growth factor (aFGF). We hypothesized that the novel synthetic retinoid CD437 would exert its apoptotic effect by reducing the activity of Akt. We further hypothesized that aFGF would protect against CD437 apoptosis by preserving the activity of Akt. Initially we demonstrated that CD437 produces apoptotic cell death in NIH 3T3 fibroblasts, and that this effect is attenuated in fibroblasts transfected to express aFGF. Next we assessed Akt activity and showed that phospho-Akt is significantly reduced in 3T3 cells exposed to CD437. We showed that this effect is less pronounced in aFGF transfected 3T3 cells. Furthermore, we observed that the addition of exogenous aFGF to 3T3 cells significantly increases Akt phosphorylation. These findings tend to confirm our hypothesis that reduction in Akt activation is a mechanism involved in the apoptotic effect of the retinoid CD437, and that preservation of Akt phosphorylation occurs in response to aFGF and appears to explain the partially protective effect of aFGF for 3T3 cells vis a vis CD437.

Success and limitations of a naked plasmid transfection protocol for keratinocyte growth factor-1 to enhance cutaneous wound healing.

Our group and others have previously reported enhancement of cutaneous wound healing following the transfection of tissue with plasmid vectors expressing the DNA for growth factors. In these experiments, growth factor treated animals were usually compared to animals treated with control plasmid vector. To achieve consistent transfection, high DNA plasmid load and repeated penetrations of the wound by needle or gene gun were required. In the current experiments, we assessed the effect of the plasmid load and repeated tissue penetrations on wound healing of excisional wounds in diabetic C57 mice. Animals received 5 mm excisional wounds, and were assigned to the following groups, no treatment, phosphate buffered saline solution injections, and plasmid vector injection with and without the keratinocyte growth factor-1 gene. Intradermal injections of 100 microg plasmid were given adjacent to the wounds at days 1-5, 7 and 11. At day 9, wound closure was more advanced in keratinocyte growth factor-1 treated animals compared to those treated with control plasmid. But a detrimental effect of the DNA plasmid injection was evident from a comparison of the DNA control group versus the non-injected group. Therefore, the challenge for developing an effective system for the enhancement of wound healing lies in improving transfection efficiency.

Management of Barrett's esophagus.

There have been major recent advances in the understanding of the pathogenesis and epidemiology of Barrett's esophagus and adenocarcinoma of the esophagus. The advent of potent acid suppression with proton pump inhibitors and safe, minimally invasive antireflux procedures has made alleviating symptoms and eliminating peptic complications achievable goals for the vast majority of patients. Endoscopic surveillance of Barrett's esophagus is considered the standard of care and is widely used in clinical practice. Neither medical nor surgical antireflux procedures, however, result in the regression of Barrett's esophagus in any consistent manner. Thermal and chemical endoscopic ablation techniques show promise in both the management of high grade dysplasia and the reversal of Barrett's esophagus, but these techniques are still of unproven benefit, and can be costly and risky. Therefore, prospective and controlled studies with long term follow-up are needed before incorporating ablative techniques into routine clinical practice. Management of high grade dysplasia remains controversial. Alternative management strategies include surveillance, resection or ablation, tailored to the individual patient and the available expertise. Targets for future research include defining appropriate surveillance intervals; finding biological markers that identify patients at higher risk of progressing to cancer; defining the cancer risk and the appropriate management of patients with short segment Barrett's esophagus; understanding the natural history of dysplasia and comparing alternatives for the management of high grade dysplasia; and studying whether surgical management can delay or prevent the progression to dysplasia and adenocarcinoma.

Intratumoral therapy of cisplatin/epinephrine injectable gel for palliation in patients with obstructive esophageal cancer.

Obstructing esophageal cancer produces severe dysphagia with ensuing death within 90 days. Palliation is possible with modalities like stent placement, laser, and photodynamic therapy. However, these treatments have a high rate of complications, and the overall mortality is not altered. A new alternative treatment evaluated in this study is endoscopic intratumoral injection with cisplatin/epinephrine (CDDP/epi) gel. CDDP/epi gel injections were administered weekly for 3 to 8 weeks in nine patients, median age, 72 years; mean tumor volume (+/-SEM), 41.44 (+/-22.4) cm3. Eight patients had stage IV, and one had stage III esophageal carcinoma. The mean dysphagia score (+/-SEM) was 3.5 (+/-0.17). All patients were followed up until death. Dysphagia resolved in eight patients with reduction in mean dysphagia score (+/-SEM) from 3.5 (+/-0.17) to 0.75 (+/-0.28; p = 0.005). Tumor volume was reduced by 75% in one patient and by 50% in two patients. The median survival was 4 months. The longest follow-up has been 15 months (458 days). In this pilot study, intratumoral injection of CDDP/epi gel restored swallowing in eight of nine patients and was an effective and safe outpatient treatment in patients with obstructive esophageal cancer.

Esophagogastric adenocarcinoma in an E1A/E1B transgenic model involves p53 disruption.

We studied tumorigenesis and p53 immunostaining in a murine transgenic model introducing E1A/E1B under the control of the mouse mammary tumor virus-long terminal repeat (MMTV-LTR) promoter in which adenocarcinoma occurs at the squamocolumnar junction in the foregut, predominantly in males, and at no other site. Mutations of p53 are frequent in human esophageal adenocarcinoma and the E1B gene product interferes with p53-mediated apoptosis, inhibiting tumor suppression at the G(1)/S checkpoint. Transgenic animals were generated utilizing a purified linear 6.7 kb fragment of plasmid DNA containing MMTV-LTR/E1A/E1B and were confirmed by dot blot hybridization of tail DNA to (32)P-labeled E1A/E1B probe and polymerase chain reaction (PCR) amplification of E1A. Transgenic and control animals were observed for morbidity and weight changes. Eleven of 45 animals were transgenic (24% efficiency) with an estimated 5 to 57 copies of the gene per genome. Profound weight loss (>20%) led to sacrifice or death of one of five females (at 12 weeks) and four of six males (at 16 to 17 weeks). Grossly visible tumors (2 to 10 mm) were noted in the forestomach at the visible margin between the proximal (squamous-lined) stomach and the distal glandular stomach. Histologic sections confirmed adenocarcinoma arising in each case at the squamocolumnar junction with glandular formation, pleomorphism, and frequent mitotic figures. Immunostaining was positive for p53 indicating accumulation of mutated or altered p53 protein. E1A/E1B transgenic animals developed macroscopic and microscopic adenocarcinoma at the squamocolumnar junction, which corresponds to adenocarcinoma at the human esophagogastric junction. Disruption of p53 was present in the transgenic model as in the human cancer.

Hospital volume can serve as a surrogate for surgeon volume for achieving excellent outcomes in colorectal resection.

OBJECTIVE: To examine the association of surgeon and hospital case volumes with the short-term outcomes of in-hospital death, total hospital charges, and length of stay for resection of colorectal carcinoma. METHODS: The study design was a cross-sectional analysis of all adult patients who underwent resection for colorectal cancer using Maryland state discharge data from 1992 to 1996. Cases were divided into three groups based on annual surgeon case volume--low (< or =5), medium (5 to 10), and high (>10)--and hospital volume--low (<40), medium (40 to 70), and high (> or =70). Poisson and multiple linear regression analyses were used to identify differences in outcomes among volume groups while adjusting for variations in type of resections performed, cancer stage, patient comorbidities, urgency of admission, and patient demographic variables. RESULTS: During the 5-year period, 9739 resections were performed by 812 surgeons at 50 hospitals. The majority of surgeons (81%) and hospitals (58%) were in the low-volume group. The low-volume surgeons operated on 3461 of the 9739 total patients (36%) at an average rate of 1.8 cases per year. Higher surgeon volume was associated with significant improvement in all three outcomes (in-hospital death, length of stay, and cost). Medium-volume surgeons achieved results equivalent to high-volume surgeons when they operated in high- or medium-volume hospitals. CONCLUSIONS: A skewed distribution of case volumes by surgeon was found in this study of patients who underwent resection for large bowel cancer in Maryland. The majority of these surgeons performed very few operations for colorectal cancer per year, whereas a minority performed >10 cases per year. Medium-volume surgeons achieved excellent outcomes similar to high-volume surgeons when operating in medium-volume or high-volume hospitals, but not in low-volume hospitals. The results of low-volume surgeons improved with increasing hospital volume but never equaled those of the high-volume surgeons.

Utility of magnetic resonance cholangiography in the evaluation of biliary obstruction.

BACKGROUND: Evaluation of suspected biliary obstruction has traditionally involved a variety of imaging modalities including ultrasound, CT, and invasive cholangiography. These techniques have limitations because of poor visualization of intraductal stones (ultrasound and CT) and the need for an invasive procedure (ERCP and percutaneous transhepatic cholangiography). Magnetic resonance cholangiography (MRC) is a noninvasive imaging modality that provides good visualization of the hepatobiliary system. The aim of the present study was to determine the utility of MRC in evaluating patients with suspected biliary obstruction. STUDY DESIGN: One hundred forty-three patients were identified with suspected acute biliary obstruction and underwent MRC. Patient selection was based on clinical criteria including an elevation in serum liver chemistries or evidence of biliary ductal dilatation on conventional imaging. MRC was performed using a half-Fourier acquisition single-shot turbo spin-echo sequence involving single breath-hold rapid image acquisition. A final diagnosis was determined in each patient based on invasive cholangiography, findings at surgery, and clinical course. RESULTS: Of the 143 patients, 73 had an obstructing biliary lesion. A malignant process was identified in 25 patients with final diagnoses of pancreatic cancer (n = 15), ampullary cancer (n = 4), cholangiocarcinoma (n = 3), and hepatic or nodal metastases (n = 3). MRC correctly identified biliary obstruction in all these patients and accurately identified the level of biliary obstruction in 24 of 25 patients. Based on the MRC images alone, a malignant process was suspected in 21 of the 25 patients. Forty patients were found to have common bile duct stones and eight patients had a benign distal bile duct stricture. MRC correctly identified common bile duct stones in 37 patients with one false-positive exam (sensitivity = 92%; specificity = 99%). MRC also correctly identified distal biliary strictures in eight patients. In the remaining 70 patients, no definite biliary obstruction was identified by MRC, and in all patients the absence of mechanical obstruction was confirmed by invasive cholangiography or overall clinical course. CONCLUSIONS: This study demonstrates that MRC is able to accurately identify the level and cause of biliary obstruction in both malignant and benign disease. MRC may prove to be an important noninvasive tool in preoperative evaluation of patients with suspected biliary obstruction and identification of patients most likely to benefit from an invasive radiologic or surgical procedure.

Surgical intervention and understanding of diseases of the stomach and duodenum.

The stomach and duodenum are organs of complex physiology and cell biology. Neoplastic disease of these organs represents a difficult surgical challenge, and gastric and duodenal cancer mortality rates remain high despite advances in surgical technique, perioperative care, and adjuvant therapy. True "cures" elude the surgeon all too often. Fortunately, our understanding of the genetics and molecular biology of upper gastrointestinal neoplasms is increasing and is now significantly affecting the clinical management of these tumors as surgical therapies continue to improve. The care of benign disease of the stomach and duodenum is also evolving as medical therapy and surgical technology improve to lessen the morbidity associated with peptic ulcer disease and other benign conditions. The event that may have the greatest effect on surgical intervention in peptic ulcer disease is the Centers for Disease Control and Prevention launching of an educational campaign to promote treatment of Helicobacter pylori. This article reviews the most significant advances published in the past year on surgical intervention of the stomach and duodenum.

Characterization of an aFGF gene expression vector with therapeutic potential.

BACKGROUND: Topical application of growth factors to wounds has proven to be suboptimal in achieving epithelial growth and accelerating healing. We propose transfection of fibroblasts with a gene for acidic fibroblast growth factor (aFGF) which will allow continuous, local delivery of the growth factor to wounds, ulcerative lesions, or healing tissues. METHODS: We utilized a pMEXneo vector containing the human aFGF gene with a secretory signal sequence from the hst/KS3 gene to obtain continuous secretion of therapeutic doses of aFGF. NIH 3T3 fibroblasts were transfected using a liposomal transfection reagent and grown in selective media. RESULTS: Dot blot hybridization with labeled complementary DNA probes revealed the presence of plasmid DNA in transfected but not wild type fibroblasts. Intracellular concentrations of aFGF remained low in transfected cells; however, the media contained high levels (32 +/- 7 nM) of aFGF as measured by ELISA. Concentrations of aFGF capable of stimulating cell proliferation were maintained for several weeks. CONCLUSIONS: The aFGF cDNA was transcribed and translated into a functional polypeptide that is secreted from NIH 3T3 cells at physiologically significant concentrations. Stable transfection with a eukaryotic vector which induces secretion of aFGF at levels promoting cell growth holds promise for clinical application in wounds or healing tissue. Transfection could be achieved by topical or endoscopic injection of this type of vector.

Role of insulin-like growth factor-I in esophageal mucosal healing processes.

The current study examines the stimulation of healing processes and signal transduction that is mediated by insulin-like growth factor-I (IGF-I) in an ex vivo esophageal explant model when using tyrphostin inhibition of receptor tyrosine kinase. The explant model provides a 3-dimensional cellular environment of multiple interacting cells isolated from the neural and vascular supply. Tyrphostins previously characterized for their interactions with epithelial growth factor (EGF) receptor-associated protein tyrosine kinases were tested for their potential effects on IGF-I growth-promoting activity. Explants of rabbit esophagus were incubated in media with or without IGF-I. Tyrphostins 1, 23, 25, 46, 47, 51, and 63 were added. We assessed DNA synthesis by tritiated thymidine incorporation. Outgrowth from the edge of the primary mucosa of the explant was evaluated on histologic sections, and cell proliferation was confirmed with immunohistology. IGF-I increased the incorporation of tritiated thymidine by 50% to 100%. Tyrphostins 23 and 47 eliminated IGF-I-induced proliferation in a dose-dependent manner. Tyrphostins 25, 46, and 51--along with negative controls tyrphostin 1 and tyrphostin 63--were ineffective, inasmuch as IGF-I-stimulated growth remained unchanged in their presence. Proliferative activity demonstrated by PCNA staining was confined to new mucosa. Two of 5 tyrphostins originally developed as EGF receptor protein tyrosine kinase inhibitors were effective in inhibiting the actions of exogenous IGF-I. We conclude that IGF-I stimulation may play an important role in repair processes in the esophagus and that this stimulation can be inhibited by using specific tyrphostins.