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This study was designed to assess the potential relationship between the late loss of angiographic luminal diameter and biochemical abnormalities of arterial wall collagen in rabbits subjected to angioplasty, and to test the hypothesis that beta-aminopropionitrile (beta APN), an inhibitor of lysyl oxidase, would inhibit such changes when administered orally for 1 mo after angioplasty. Endovascular injury was induced in rabbit iliac arteries by ipsilateral balloon angioplasty (BA) and by contralateral balloon angioplasty accompanied by exposure to continuous wave neodymium: yttrium aluminum garnet laser radiation (LBA). Computer measurement of angiographic luminal diameter demonstrated significant vessel narrowing at 1 and 6 mo after both procedures. By quantitative histology, the majority of the 1-mo loss in angiographic diameter could not be attributed to neointimal thickening. Analysis of collagen cross-linking by HPLC in collagen obtained from the LBA-injured segments of the arteries 1 mo after angioplasty revealed a significant increase, relative to values from uninjured arteries (P < 0.05), in the difunctional cross-link dihydroxylysinonorleucine (DHLNL). 6 mo after angioplasty, the content of hydroxypyridinium, the trifunctional maturational product of DHLNL, was significantly elevated in both BA- and LBA-treated arteries compared with values from uninjured arteries (P < 0.05). In animals administered beta APN, luminal narrowing at 1 mo, compared with controls, was attenuated (P < 0.01) and DHLNL content was decreased (P < 0.05) in arteries subjected to LBA, but not in arteries subjected to BA. The results suggest that lathyrogenic agents may be efficacious in favorably modulating LBA-induced alterations in vessel diameter and mural connective tissue.

To test the hypothesis that bone mineral density (BMD) in periarticular subchondral regions of the knee joint is abnormal in patients with osteoarthritis (OA).Sixty-two knees from patients with relatively mild OA (primarily radiographic grades 0, 1, 2) of the knee were compared with 62 knees from normal subjects matched for age, sex, race, and body side (right or left). BMD of the lumbar spine, distal femoral shaft, and several periarticular subchondral regions of the knee were determined by dual energy x-ray absorptiometry (DXA). To facilitate increased accuracy of BMD values, lateral DXA of the knees was also performed and used to provide a third dimension to the usual two-dimensional anterior-posterior g/cm2, producing measurements as g/cm3. Subchondral bone regions included both superficial and deep regions of the medial femoral, medial tibial, and lateral tibial compartments.BMD (g/cm3) was lower than normal in 6 subchondral bone regions of the knees (n=43) of white female patients with OA (average decrease -13.3%), significant in all 6 subchondral regions (p=0.001 to p=0.047). Two-dimensional BMD (g/cm2) was lower than normal in 6 subchondral regions of the knees (n=43) of white female patients with OA (average decrease -7.3%), significant in only 2 of 6 subchondral regions (p=0.011 to p=0.014). BMD (g/cm3) was lower than normal in 6 subchondral regions of the knees (n=19) of African American female patients with OA (average decrease -9.1%), significant in only one of the 6 subchondral regions (p=0.016). There was no significant difference in spinal BMD (L1-L4) or femoral shaft BMD between normal and OA for either racial group. About 13% of the OA patients had osteoporosis at the spine.A significant decrease in periarticular subchondral BMD is present in female patients with relatively mild OA of the knee whether or not they had osteoporosis based on a spine BMD measurement.

T cell receptor (V beta) use in the response to type II collagen and cartilage proteoglycans was analysed in peripheral blood and synovial fluid T cells from RA patients. T cells from RA patients with an immune response to connective tissue antigens, and paired PB and SF samples were stimulated in vitro with type II collagen, high density aggrecan proteoglycans (PG), and the T cell mitogen concanavalin A. After short term culture, mRNA was extracted from cells and a reverse transcription-polymerase chain reaction was performed, using primers specific for eight TCR V beta determinants. Blood cells stimulated with ConA generated strong bands with virtually all the V beta primers tested, but the TCR (V beta) expression by SF T cells stimulated with mitogen was biased, suggesting a selection process during joint infiltration. The V beta phenotypes of cells responding to PG was restricted in individual RA patients, but the pattern of V beta use in the the RA population was not consistent. In contrast, the V beta phenotypes of SF cells responding to CII was highly biased in both individual patients and the RA population, with V beta 14, V beta 17, and V beta 8 phenotypes predominant. We conclude that the T cell response to connective tissue antigens is restricted compared with mitogen stimulation, with the highest degree of TCR bias seen in the response of SF T cells to stimulation with type II collagen.

Autoantibodies have been described in human cancer patients as well as in animal models of malignancy. The extracellular matrix and especially basement membranes act as barriers for tumor cell invasion. Collagen, particularly types I, III, and IV, are major constituents of the extracellular matrix. We tested the hypothesis that autoimmunity to collagen antigens is present in lung cancer. Sera from 67 patients with lung cancer and 50 reference subjects were tested for anticollagen antibodies by using purified human collagen types I-V and for antibodies binding human cartilage aggrecan proteoglycan. Antibody levels were determined by using ELISA. The relationship of serum levels of these antibodies to patient survival, histology, treatment response, disease stage, and pack years of smoking was examined by using multiple regression and discriminant function analyses. A subgroup of 45 patients in whom a smoking history was available was analyzed separately. Within 1 month of the initiation of therapy, mean serum levels of antibodies binding fibrillar collagen types I-III and V were significantly higher (P0.025) than were those in control sera (43.2% of patients positive for one or more anticollagen antibodies). Antibodies binding aggrecan proteoglycan were not different between patients and control sera. In the lung cancer patients, the levels of serum antibodies binding types IV and V collagens contributed to the variance of progression-free survival days, survival days, and the duration of favorable response in opposite directions. Histological cell type contributed to the variance in the level of serum antibody binding collagen types IV and V. Lower levels of antibody binding type IV and higher levels of antibody binding type V were associated with small cell carcinoma. The pack-years of smoking only contributed to the variance in the level of serum antibody binding type V collagen. We conclude that autoantibodies to fibrillar collagen antigens are present frequently in lung cancer patients, and their levels may be related to histological cell type and to the duration of the response to treatment.

To test the hypothesis that both aging and osteoarthritis (OA) contribute to the variance of human articular cartilage thickness of the knee and whether these contributions occur predominantly at weight bearing cartilage sites.Thin, sagittal magnetic resonance images (MRI) of both knees were examined in 52 patients with idiopathic OA of the knee of short duration (87%:or = 4 years) and 40 reference subjects of comparable age and sex distribution. Articular cartilage thickness was measured at the weight bearing and nonweight bearing femoral condylar, tibial plateau, and posterior patellar sites. Multiple regression analyses were performed to examine the influence of OA, age, sex, obesity (body mass index), and bone size on cartilage thickness.Age accounted for a significant linear decrease (p0.001) in both lateral and medial weight bearing femoral cartilage thickness of both knees, but failed to account for any significant variance in thickness at other cartilage sites. OA accounted for a significant decrease (p0.02) in the thickness of the femoral articular cartilage in the medial and lateral right knee compartments and in the lateral left knee compartment, but not in the medial left knee compartment. Significant cartilage thinning could be detected by MRI in patients with OA, even when the joint space was normal radiographically.The asymmetric decrease in the left knee may reflect the effect of mechanical factors. Our data show that articular cartilage thickness decreases at the femoral weight bearing sites both with age and as a consequence of OA and that these contributions can be distinguished from one another.

The occurrence of rheumatoid arthritis (RA) and the extent of antecedent lymphoid surgeries was examined using case control study methods. Two hundred sixty-four patients with definite or classic RA were considered and 283 patients with rheumatic diseases presumably of nonimmunologic origin were used as controls. The odds for developing RA were found to be significantly higher for patients with multiple lymphoid surgeries (tonsillectomy and adenoidectomy or tonsillectomy and adenoidectomy plus appendectomy) and exhibited a gradient, increasing with more extensive surgery. Significant rank correlations were found in patients with RA between the age at tonsillectomy and the rheumatoid factor (RF) titer. An earlier tonsillectomy correlated with lower titers of RF. A significant decrease of serum RF titer was also seen in patients with RA subjected to tonsillectomy, adenoidectomy and appendectomy. We conclude that antecedent removal of lymphoid tissue from the tonsils, adenoids and appendix constitutes a risk factor predisposing to RA. Moreover, this risk seems related to the quantity of lymphoid tissue removed.

An animal model of pulmonary radiation fibrosis was established, using male CBA/j mice. Both lungs of each mouse in one group (DL) were irradiated with two doses of 8.5 Gy each, separated by 30 days. A control group (CG) was sham-irradiated. There was a small but significant difference (P less than 0.03) in average breathing rate between DL and CG 27 weeks after the second irradiation which increased until the 34th week followed by a plateau. The accumulated hydroxyproline content of the irradiated mouse lung was 40% greater (P less than 0.02) than that of the sham-irradiated lung at 42 weeks and thereafter. Anticollagen antibodies assayed 52 weeks after irradiation by enzyme-linked immunosorbent assay were elevated by 49% in sera from the irradiated mice compared to sera from sham-irradiated mice. Mortality during the 52-week period following the second irradiation was low (13%) for both groups. Histological comparison of irradiated and control mouse lungs fixed under uniform inflation pressure indicated no significant differences. The model has unique features including an increase in collagen deposition, no acute changes attributable to radiation, a small but statistically significant abnormality in pulmonary function, an immunologic response to collagen, and low mortality.

An animal model of pulmonary radiation fibrosis was established, using male CBA/j mice. Both lungs of each mouse in one group (DL) were irradiated with two doses of 8.5 Gy each, separated by 30 days. A control group (CG) was sham-irradiated. There was a small but significant difference (P less than 0.03) in average breathing rate between DL and CG 27 weeks after the second irradiation which increased until the 34th week followed by a plateau. The accumulated hydroxyproline content of the irradiated mouse lung was 40% greater (P less than 0.02) than that of the sham-irradiated lung at 42 weeks and thereafter. Anticollagen antibodies assayed 52 weeks after irradiation by enzyme-linked immunosorbent assay were elevated by 49% in sera from the irradiated mice compared to sera from sham-irradiated mice. Mortality during the 52-week period following the second irradiation was low (13%) for both groups. Histological comparison of irradiated and control mouse lungs fixed under uniform inflation pressure indicated no significant differences. The model has unique features including an increase in collagen deposition, no acute changes attributable to radiation, a small but statistically significant abnormality in pulmonary function, an immunologic response to collagen, and low mortality.