Presence Of Inflammatory Infiltrate Research Articles

A new link between cancer and inflammation?

Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Rebouissou S, Amessou M, Couchy G, Poussin K, Imbeaud S, Pilati C, Izard T, Balabaud C, Bioulac-Sage P, Zucman-Rossi J. Inflammatory hepatocellular adenomas are benign liver tumours defined by the presence of inflammatory infiltrates and by the increased expression of inflammatory proteins in tumour hepatocytes. Here we show a marked activation of the interleukin (IL)-6 signalling pathway in this tumour type; sequencing candidate genes pinpointed this response to somatic gain-of-function mutations in the IL6ST gene, which encodes the signalling co-receptor gp130. Indeed, 60% of inflammatory hepatocellular adenomas harbour small in-frame deletions that target the binding site of gp130 for IL-6, and expression of four different gp130 mutants in hepatocellular cells activates signal transducer and activator of transcription 3 (STAT3) in the absence of ligand. Furthermore, analysis of hepatocellular carcinomas revealed that rare gp130 alterations are always accompanied by beta-catenin-activating mutations, suggesting a cooperative effect of these signalling pathways in the malignant conversion of hepatocytes. The recurrent gain-of-function gp130 mutations in these human hepatocellular adenomas fully explains activation of the acute inflammatory phase observed in tumourous hepatocytes, and suggests that similar alterations may occur in other inflammatory epithelial tumours with STAT3 activation. [Abstract reproduced by permission of Nature 2009;457:200–204.]

Homocysteine induces oxidative stress, inflammatory infiltration, fibrosis and reduces glycogen/glycoprotein content in liver of rats

Hyperhomocysteinemia has been related to various diseases, including homocystinuria, neurodegenerative and hepatic diseases. In the present study we initially investigated the effect of chronic homocysteine administration on some parameters of oxidative stress, named total radical-trapping antioxidant potential, total antioxidant reactivity, catalase activity, chemiluminescence, thiobarbituric acid-reactive substances, and total thiol content in liver of rats. We also performed histological analysis, evaluating steatosis, inflammatory infiltration, fibrosis, and glycogen/glycoprotein content in liver tissue sections from hyperhomocysteinemic rats. Finally, we evaluated the activities of aminotransferases in liver and plasma of hyperhomocysteinemic rats. Wistar rats received daily subcutaneous injection of Hcy from their 6th to their 28th day of life. Twelve hours after the last injection the rats were sacrificed, liver and plasma were collected. Hyperhomocysteinemia decreased antioxidant defenses and total thiol content, and increased lipid peroxidation in liver of rats, characterizing a reliable oxidative stress. Histological analysis indicated the presence of inflammatory infiltrate, fibrosis and reduced content of glycogen/glycoprotein in liver tissue sections from hyperhomocysteinemic rats. Aminotransferases activities were not altered by homocysteine. Our data showed a consistent profile of liver injury elicited by homocysteine, which could contribute to explain, at least in part, the mechanisms involved in human liver diseases associated to hyperhomocysteinemia.

Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours

Inflammatory hepatocellular adenomas are benign liver tumours defined by the presence of inflammatory infiltrates and by the increased expression of inflammatory proteins in tumour hepatocytes. Here we show a marked activation of the interleukin (IL)-6 signalling pathway in this tumour type; sequencing candidate genes pinpointed this response to somatic gain-of-function mutations in the IL6ST gene, which encodes the signalling co-receptor gp130. Indeed, 60% of inflammatory hepatocellular adenomas harbour small in-frame deletions that target the binding site of gp130 for IL-6, and expression of four different gp130 mutants in hepatocellular cells activates signal transducer and activator of transcription 3 (STAT3) in the absence of ligand. Furthermore, analysis of hepatocellular carcinomas revealed that rare gp130 alterations are always accompanied by beta-catenin-activating mutations, suggesting a cooperative effect of these signalling pathways in the malignant conversion of hepatocytes. The recurrent gain-of-function gp130 mutations in these human hepatocellular adenomas fully explains activation of the acute inflammatory phase observed in tumourous hepatocytes, and suggests that similar alterations may occur in other inflammatory epithelial tumours with STAT3 activation.

Dystrophic-Like Alterations Characterize Orbicularis Oris and Palatopharyngeal Muscles in Patients Affected by Cleft Lip and Palate

This study analyzed histological and histochemical features of specimens of the orbicularis oris muscle, and palatal and pharyngeal muscles biopsied during surgery from 33 patients affected by cleft lip and palate. Three groups were studied: 20 patients affected by cleft palate with or without cleft lip (at the time of primary palatoplasty), seven by cleft lip with or without cleft palate (primary lip closure), and six by cleft lip with or without cleft palate (secondary cheiloplasty). Muscle sections were stained with hematoxylin-eosin, modified Gomori trichrome, ATPase reaction at pH 9.4, and NADH-TR. Analyzed parameters included organization, muscle fiber size and type, nuclear changes, presence of ragged-red fibers, degree of fibrosis, and presence of inflammatory infiltrate. In all patients who underwent primary palatoplasty and lip closure we noted dystrophic-like alterations of orbicularis oris and palatopharyngeal muscles, such as variability of fiber size, fiber disorganization, and increased fibrosis. The same alterations were found in adult patients submitted to secondary cheiloplasty, notwithstanding surgical repair. Furthermore, in all groups neither neurogenic atrophy nor ragged-red fibers or inflammatory infiltrate were detected. Muscle damage is a constant event in this deformity, and it could play an important role in its etiopathogenesis. Muscular biopsy during cheiloplasty and palatoplasty could offer useful information about muscle condition and possible functional recovery in cleft lip and palate patients.

Antipruritic effect of cyclosporine microemulsion in prurigo nodularis: Results of a case series

Prurigo nodularis shows intense itching nodules, which are often persistent and therapy refractory. Histological alterations include fibrosis of collagen fibers and presence of inflammatory infiltrate, which partly explains the clinical persistence of lesions. Inflammatory cells may directly contribute to induction and maintenance of pruritus at nerve fibers. Cyclosporine microemulsion (ME) suppresses the migration and proliferation of inflammatory cells and may thereby interfere with pathogenesis of prurigo nodularis. The aim of this investigation was to assess the antipruritic efficiency of cyclosporine ME in therapy of prurigo nodularis. 14 patients with prurigo nodularis of diverse origin and failure to previous therapy were treated with oral cyclosporine ME (3 to 5 mg per kg daily). Blood pressure, liver enzymes, renal function and differential blood count were monitored. In 13 of 14 prurigo patients (92.9 %) there was a significant response to monotherapy with cyclosporine ME. The maximal antipruritic effect occurred after 2 weeks to 12 months. Prurigo nodules also healed during therapy. Seven patients (50.0 %) described side effects. In one case the therapy was stopped. Oral cyclosporine ME is an effective therapy for prurigo nodularis of diverse origin. It appears to function by inhibiting dermal inflammatory cells.

Clinical Variables Associated With the Presence of Inflammatory Infiltrates in Patients With Dilated Cardiomyopathy Undergoing Heart Transplantation

Introduction Idiopathic dilated cardiomyopathy (DCM) is, together with ischemic heart disease, the major cause of end-stage heart failure leading to heart transplantation. However, an unknown percentage of patients with this diagnosis has inflammatory foci found in the histopathological study of the explanted heart. This fact suggests an undetected process of acute myocarditis as the cause of cardiac dysfunction. Objective The objective of this study was to identify clinical and echocardiographic variables related to the presence of myocardial infiltrates, as a potential guide to determine which patients should undergo endomyocardial biopsy in DCM. Materials and Methods We retrospectively analyzed 161 patients who underwent heart transplantation with a diagnosis of DCM between 1987 and 2007. The presence of inflammatory infiltrates was considered significant when the histopathological study of tissue blocks from the left ventricle showed 1 or more foci per cm 2 of perivascular or interstitial mononuclear or polymorphonuclear cells, whether or not in the presence of cytolysis. Results Seventeen patients (11%) had these inflammatory histological findings; of them, 6 (35%) showed preponderance of eosinophils and 7 (41%) showed areas of cytolysis. The DCM group with inflammatory infiltrates showed significant differences in terms of younger age (45 ± 15 vs 50 ± 11 years; P < .01) and smaller ventricular diameters ( P < .05). Male gender was more frequent in this group, and the patients had a poorer clinical status and greater dependence on inotropic drugs. Conclusions Inflammatory infiltrates are frequently present in DCM explanted hearts. Although there are no relevant clinical variables to identify subclinical myocarditis, these patients are younger and have smaller ventricular diameters and poorer functional status at the time of transplantation.

Role of cervicitis in the Raman-based optical diagnosis of cervical intraepithelial neoplasia

The Raman-based optical diagnosis of normal cervix, inflammative cervix (cervicitis), and cervical intraepithelial neoplasia was investigated on samples of 63 patients. The main alterations were found in the 857 cm(-1) (CCH deformation aromatic); 925 cm(-1) (C-C stretching); approximately 1247 cm(-1) (CN stretch, NH bending of Amide III); 1370 cm(-1) (CH2 bending); and 1525 cm(-1) (C=CC=N stretching) vibrational bands in accordance with previously reported in the literature comparing normal and malignant cervical tissue. The statistical analysis (principal components analysis, clustering, and logistic regression models) applied to the spectral data indicated that the full discrimination among normal and neoplastic tissues of cervix by Raman optical biopsy is seriously affected by the presence of inflammatory infiltrates, which increases the false-positive rate. This fact is specially relevant once cervicitis is a very common state (noncancerous) of the cervix of sexually active woman. The results suggest that, for the correct Raman-based diagnosis of normal cervix from cervical intraepithelial neoplasia, it is necessary to use an auxiliary way to discriminate the contribution from the inflammatory infiltrates.

Transient Receptor Potential Vanilloid 1 Mediates Hyperalgesia and Is Up-Regulated in Rats With Chronic Pancreatitis

The neurobiologic basis of pancreatic hyperalgesia in chronic pancreatitis (CP) is understood poorly and there is a need to identify novel therapeutic targets. Our aim was to study the role of the transient receptor potential vanilloid 1 (TRPV1), a key integrator of noxious stimuli, in the pathogenesis of pancreatic pain in a rat model of CP. CP was induced in rats by intraductal injection of trinitrobenzene sulfonic acid. TRPV1 currents in pancreas-specific DRG neurons were measured using perforated patch-clamp techniques. Reverse-transcription polymerase chain reaction was used to measure mRNA expression of TRPV1 in these neurons after laser capture microdissection. Immunofluorescence and Western blot analysis, using TRPV1-specific antibodies, also were performed. Pancreatic hyperalgesia was assessed by rat's nocifensive behavior to electrical stimulation of the pancreas. CP was associated with a 4-fold increase in capsaicin-induced current density (P < .02), along with an increase in the proportion of pancreas-specific DRG neurons that responded to capsaicin (52.9% in controls vs 79.0% in CP; P < .05). CP also was associated with a significant increase in TRPV1 expression both at the messenger RNA and protein level in whole thoracic DRGs and pancreas-specific sensory neurons. Systemic administration of the TRPV1 antagonist SB-366791 markedly reduced both visceral pain behavior and referred somatic hyperalgesia in rats with CP, but not in control animals. TRPV1 up-regulation and sensitization is a specific molecular mechanism contributing to hyperalgesia in CP and represents a useful target for treating pancreatic hyperalgesia caused by inflammation.

Isolated giant xanthogranuloma of the orbit

Xanthogranuloma is an uncommon tumor in the orbit and is usually associated with systemic diseases or blood abnormalities. We report an extremely rare presentation of isolated orbital xanthogranuloma unassociated with any systemic disease, hematological or biochemical abnormalities. A 47-year-old physician presented with proptosis of the left eye of three years duration with yellowish skin plaques. The CT scan revealed a well-defined heterogeneous mass in the medial orbit. There was no evidence of systemic, serum or biochemical abnormalities. The mass was removed by a medial orbitotomy. Histopathology confirmed the diagnosis based on the presence of inflammatory infiltrates, histiocytes and Touton giant cells.

Histologic Response to Injected Phosphatidylcholine in Fat Tissue: Experimental Study in a New Rabbit Model

The application of phosphatidylcholine to the fat tissue of humans for aesthetic purposes has recently been in evidence, despite the sparse literature corroboration of this practice. The authors developed a new experimental model to study injection of substances in fat tissue in rabbits. The objective of this particular study was to verify the possible effects of phosphatidylcholine injected in the animals. The animal weight, the fat pad weight, the presence of inflammatory infiltrate, and fibrosis and necrosis at the application sites were observed. Two groups of rabbits received five weekly applications to the dorsal fat pad. The control group received saline solution 0.9%, and the study group received phosphatidylcholine. The removed fat tissue was evaluated 3, 7, 14, and 21 days after the fifth application was completed. The phosphatidylcholine group presented more intense inflammatory infiltrate and fibrosis than the control group (p = 0.05). Necrosis was not observed in any animal. There was no statistically significant difference with regard to the weights of the animal or the fat pad. On the basis of this study, the injection of phosphatidylcholine is relatively safe, but no effect was observed regarding the reduction of fat tissue volume. New studies with higher doses are needed to justify the clinical use of this substance.

TNF-α Is Necessary for Induction of Coronary Artery Inflammation and Aneurysm Formation in an Animal Model of Kawasaki Disease

Kawasaki disease is the most common cause of multisystem vasculitis in childhood. The resultant coronary artery lesions make Kawasaki disease the leading cause of acquired heart disease in children in the developed world. TNF-alpha is a pleiotropic inflammatory cytokine elevated during the acute phase of Kawasaki disease. In this study, we report rapid production of TNF-alpha in the peripheral immune system after disease induction in a murine model of Kawasaki disease. This immune response becomes site directed, with migration to the coronary arteries dependent on TNF-alpha-mediated events. Production of TNF-alpha in the heart is coincident with the presence of inflammatory infiltrate at the coronary arteries, which persists during development of aneurysms. More importantly, inflammation and elastin breakdown in the coronary vessels are completely eliminated in the absence of TNF-alpha effector functions. Mice treated with the TNF-alpha-blocking agent etanercept, as well as TNFRI knockout mice, are resistant to development of both coronary arteritis and coronary aneurysm formation. Taken together, TNF-alpha is necessary for the development of coronary artery lesions in an animal model of Kawasaki disease. These findings have important implications for potential new therapeutic interventions in children with Kawasaki disease.

The Value of Myenteric Plexitis to Predict Early Postoperative Crohn’s Disease Recurrence

Early ileocolonoscopy allows detection of recurrence after surgically induced remission of Crohn's disease (CD). Unequivocal histologic markers predicting recurrence have not been identified. We assessed the predictive value of neural lesions for early endoscopic CD recurrence and long-term reintervention risk. Ileocolonic resection specimens from 59 patients with CD and 21 control patients were histologically scored for typical inflammatory bowel disease lesions, neural hypertrophy, and presence and severity of inflamed ganglia and nerve bundles. Endoscopic recurrence was determined at 3 months in all patients and at 1 year in 32 patients as part of 2 prospective clinical trials. Myenteric plexitis of the proximal resection margin was present in 32 patients with CD (54%) in absence of surrounding inflammation. Patients with this feature had a higher endoscopic recurrence (Rutgeerts score >/=2) at 3 months (75% vs 41%; odds ratio, 4.36; 95% confidence interval, 1.44-13.23; P = .008) and at 1 year (93% vs 59%; odds ratio, 9.80; 95% confidence interval, 1.04-92.70; P = .041) and had a trend toward an earlier reintervention (mean, 7.00 vs 5.30 years; P = .174). The severity of myenteric plexitis in the proximal resection margin correlated with the severity of endoscopic recurrence at 3 months (r = 0.334, P = .010) and 1 year (r = 0.560, P = .001). Myenteric plexitis was the only consistent predictor of endoscopic recurrence. The presence of myenteric plexitis in proximal margins of ileocolonic resection specimens is predictive of early endoscopic CD recurrence.

Genotype–phenotype correlation in hepatocellular adenoma: New classification and relationship with HCC

Hepatocellular adenomas are benign tumors that can be difficult to diagnose. To refine their classification, we performed a comprehensive analysis of their genetic, pathological, and clinical features. A multicentric series of 96 liver tumors with a firm or possible diagnosis of hepatocellular adenoma was reviewed by liver pathologists. In all cases, the genes coding for hepatocyte nuclear factor 1alpha (HNF1alpha) and beta-catenin were sequenced. No tumors were mutated in both HNF1alpha and beta-catenin enabling tumors to be classified into 3 groups, according to genotype. Tumors with HNF1alpha mutations formed the most important group of adenomas (44 cases). They were phenotypically characterized by marked steatosis (P < 10(-4)), lack of cytological abnormalities (P < 10(-6)), and no inflammatory infiltrates (P < 10(-4)). In contrast, the group of tumors defined by beta-catenin activation included 13 lesions with frequent cytological abnormalities and pseudo-glandular formation (P < 10(-5)). The third group of tumors without mutation was divided into two subgroups based on the presence of inflammatory infiltrates. The subgroup of tumors consisting of 17 inflammatory lesions, resembled telangiectatic focal nodular hyperplasias, with frequent cytological abnormalities (P = 10(-3)), ductular reaction (P < 10(-2)), and dystrophic vessels (P = .02). In this classification, hepatocellular carcinoma associated with adenoma or borderline lesions between carcinoma and adenoma is found in 46% of the beta-catenin-mutated tumors whereas they are never observed in inflammatory lesions and are rarely found in HNF1alpha mutated tumors (P = .004). In conclusion, the molecular and pathological classification of hepatocellular adenomas permits the identification of strong genotype-phenotype correlations and suggests that adenomas with beta-catenin activation have a higher risk of malignant transformation.

Motor evoked potentials in a mouse model of chronic multiple sclerosis

We tested cortical motor evoked potentials (cMEPs) as a quantitative marker for in vivo monitoring of corticospinal tract damage in a murine multiple sclerosis model (experimental autoimmune encephalomyelitis, EAE). The cMEPs, previously standardized in naive C57BL/6 developing and adult mice, were studied longitudinally in adult EAE mice. Central conduction times (CCTs) increased significantly shortly before the earliest clinical signs developed (10 days postimmunization, dpi), with peak delay in acute EAE (20-40 dpi). In clinically stable disease (80 dpi), CCTs did not increase further, but cMEP amplitude declined progressively, with complete loss in >80% of mice at 120 dpi. Increase in CCT correlated with presence of inflammatory infiltrates and demyelination in acute EAE, whereas small or absent cMEPs were associated with continuing axonal damage in clinically-stabilized disease and beyond (>80 dpi). These results demonstrate that cMEPs are a useful method for monitoring corticospinal tract function in chronic-progressive EAE, and provide insight into the pathological substrate of the condition.

PERITONEAL INFLAMMATORY MYOFIBROBLASTIC TUMOR IN A BRUSH-TAILED PORCUPINE (ATHERURUS MACROURUS)

An 8-yr-old, male brush-tailed porcupine (Atherurus macrourus) presented for necropsy examination in good nutritional status. It had received treatment for Strongylus spp. infection 1 yr earlier, and it had a short episode of diarrhea 2 days before death. Postmortem examination revealed disseminated, variably discrete, soft to firm, white-gray nodules over the omentum, mesentery, intestinal serosa, and at the liver surface. Histologically, these tumors were mainly arranged as proliferating spindle cells growing in interlacing fascicles or in a storiform pattern associated with ropy collagenous stroma and vascularization. Inflammatory cells, consisting of lymphocytes, plasma cells, and macrophages, infiltrated between the tumor cells. Cytoplasmic immunoreactivity of antibodies to alpha-smooth muscle actin and vimentin was observed in the tumor cells. Antidesmin immunoreactivity varied with area. The morphologic features, the presence of inflammatory infiltrates, and the immunohistochemical expression were consistent with a diagnosis of inflammatory myofibroblastic tumor as reported in humans, horses, and cats.

Primary respiratory failure in inclusion body myositis

The idiopathic inflammatory myopathies are a group of disorders characterized by acquired muscle weakness and presence of inflammatory infiltrates in skeletal muscle.1,2⇓ The three most common diseases within this group are dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM). Respiratory muscle weakness with respiratory failure is a well-recognized complication in PM and DM but has only rarely been reported in IBM.3,4⇓ Symptomatic respiratory failure in IBM is considered to be secondary to coincidental pulmonary disease.5 We report a patient with IBM who developed subacute respiratory failure caused by primary respiratory muscle weakness. A 58-year-old woman sought treatment for slowly progressive muscle weakness, dysphagia, and weight loss. Her medical history was unremarkable, and she did not use any myotoxic drugs. Physical examination revealed normal speech, mild facial weakness, dysphagia without aspiration, and generalized muscle weakness (Medical Research Council [MRC] score, 4) with asymmetric weakness of the forearm muscles (right, MRC 4; left, MRC 3). …

Expression of interleukin-6 and tumor necrosis factor alpha and histopathologic findings in painful and nonpainful breast tissue.

Mastalgia is a common condition that is thought to be hormonally related, but the mechanisms of pain causation are unknown. Inflammatory cytokines are implicated in pain modulation, but have not been studied with regard to mastalgia. We compared the relationship of mastalgia to the expression of the cytokines interleukin (IL)-6, IL-1beta, and tumor necrosis factor (TNF)-alpha and the degree of tissue infiltration with inflammatory cells in breast tissue from 29 premenopausal women with breast pain and 29 age-matched pain-free controls. Paraffin sections from breast biopsy samples were scored for the presence of inflammatory infiltrate and were evaluated for the expression of IL-6, IL-1beta, and TNF-alpha using standard immunohistochemical procedures. TNF-alpha and IL-6 expression displayed a trend toward slightly lower values in patients with pain (median TNF-alpha score, 3 versus 5; median IL-6 score, 3 versus 4). In the luteal phase, patients with mastalgia showed a trend toward lower expression of IL-6 (p = 0.4) in comparison to those without pain. A similar trend was also seen with TNF-alpha expression (p = 0.4). IL-1beta expression was extremely scant in the first 30 samples and was not investigated further. The degree of inflammatory infiltrate in the tissue was unrelated to the presence of breast pain. These data suggest that the three cytokines tested in this study do not play a significant role in the causation of mastalgia and lend weight to the previous finding that there are no identifiable histologic correlates of this troubling condition. Further investigation of the role of cytokines in breast pain is warranted, especially in view of the possible association between mastalgia and breast cancer risk.

Inflammation and acute coronary syndromes.

The presence of inflammatory infiltrates in unstable coronary plaques suggests that inflammatory processes may contribute to the pathogenesis of these syndromes. In patients with unstable angina, coronary atherosclerotic plaques are characterized by the presence of macrophages, and to a lesser extent, T-lymphocytes, at the immediate site of either plaque rupture or superficial erosion; moreover, the rupture-related inflammatory cells are activated, indicating ongoing inflammation at the site of plaque disruption. These observations are confirmed by clinical studies demonstrating activated circulating neutrophils, lymphocytes and monocytes, and increased concentrations of pro-inflammatory cytokines, such as interleukin (IL) 1 and 6, and of acute phase reactants in patients with unstable angina and myocardial infarction. In particular elevated levels of C-reactive protein are associated with an increased risk of in-hospital and 1 to 2 years new coronary events in patients with unstable angina, but are also associated with an increased long-term risk of death and myocardial infarction in apparently normal subjects. Thus, accumulating evidence suggests that inflammation may cause local endothelial activation and, possibly, plaque fissure, leading to unstable angina and infarction. Although no information is yet available on the causes of inflammation and on its localization, these novel lines of research may open the way to a different approach to the patient with acute coronary syndromes.

Folliculotropic T cells in regressive basal cell carcinoma of skin.

The histologic features of regression may be found in some basal cell carcinomas (BCCs), and it is known that T-cell infiltrates have a significant role in host defense against this tumor. We examined 945 hair follicles (HFs) adjacent to 150 regressing BCCs of skin for the presence of inflammatory infiltrates and compared the results against 315 HFs in 50 samples of normal skin. Focal T-cell infiltrates localized mainly to the upper portion of the HFs were found in 14.5% of the follicles adjacent to regressing BCCs. A statistically significant increase of inflammation in HFs was observed in BCCs with active regression compared with BCCs with inactive and mixed regression (P < 0.05). An increase in the number of HFs involved by T lymphocytes was also found in regressing BCCs compared to normal skin ( P < 0.00005). These data suggest that the damage to the follicles is concordant with active regression of BCCs. We speculate that the immune-mediated regression of BCCs is not only specifically directed to the cells of the tumor but may also induce activated lymphocytes with cytotoxic capability to cross react with the follicular epithelium.

Immunolocalization of FGF-1 and receptors in human renal allograft vasculopathy associated with chronic rejection.

Despite recognition of chronic vasculo-occlusive disease in solid organ transplantation, the exact pathophysiologic events resulting in neointima formation remain to be elucidated. Since acidic fibroblast growth factor (FGF-1) is an established modulator of vascular cell function, we examined the expression of this growth factor and its high affinity receptors in both relevant renal transplant controls (n = 5) and tissue from patients (n = 19) who underwent nephrectomy following graft loss secondary to chronic rejection. In situ hybridization and immunohistochemical studies demonstrated minimal vascular expression and distribution of FGF-1 and FGF high affinity receptors in the normal human kidney. In contrast, vascular lesions in kidney allografts experiencing chronic rejection demonstrated the exaggerated appearance of FGF-1 ligand and receptors. Immunoreactive FGF-1 readily was detected in medial smooth muscle cells and focal areas of intimal hyperplasia, particularly in association with the presence of inflammatory infiltrate. Enhanced staining for FGF-1 mRNA primarily was associated with the appearance of resident inflammatory cells. Medial smooth muscle cells of hyperplastic vascular structures demonstrated the greatest immunoappearance of FGF receptors-however, diffuse immunostaining also was observed in areas of intimal hyperplasia. The enhanced appearance of both FGF-1 and FGF receptors in the vascular wall suggests that this polypeptide mitogen may serve as an important mediator of growth responses associated with neointima development and angiogenesis during chronic rejection of human renal allografts.