Activation of the renin-angiotensin-aldosterone system in arterial hypertension can lead to remodeling of the myocardial collagen network, with progressive collagen accumulation in the cardiac interstitium. This reactive myocardial fibrosis, which is not secondary to myocyte necrosis, appears to be an important determinant of diastolic dysfunction and thus of pathologic hypertrophy. To examine the effects of the aldosterone antagonist spironolactone on myocardial fibrosis, we analyzed interstitial fibrosis in 7 different models of arterial hypertension in rats: 2 kidney, 1 clip model of renovascular hypertension (RHT); continuous subcutaneous aldosterone (0.75 micrograms/hr) infusion; RHT and aldosterone models treated with 20 mg/kg per day of subcutaneous spironolactone; uninephrectomized rats on a high sodium diet; and age- and sex-matched controls with or without spironolactone treatment. Systolic arterial pressure was comparably elevated in RHT and aldosterone models; it was modestly lowered but not normalized by 8 weeks of spironolactone treatment at the low doses used. Such treatment also failed to prevent left ventricular hypertrophy (LVH) in all experimental groups with hypertension. Spironolactone, however, was able to prevent myocardial fibrosis in RHT and aldosterone models of acquired arterial hypertension irrespective of the development of LVH and the presence of hypertension. These findings provide further evidence that elevated aldosterone levels play an important role in the adverse remodeling of the myocardium in arterial hypertension. The antifibrotic effects of spironolactone, if confirmed in human studies, may be a valuable strategy in treating hypertensive heart disease.

Antifibrotic effects of spironolactone in preventing myocardial fibrosis in systemic arterial hypertension.

Transforming growth factor-β (TGF-β) is a potent stimulus of connective tissue accumulation, and is implicated in the pathogenesis of scleroderma and other fibrotic disorders. Smad3 functions as a key intracellular signal transducer for profibrotic TGF-β responses in normal skin fibroblasts. The potential role of Smad3 in the pathogenesis of scleroderma was investigated in Smad3-null (Smad3−/−) mice using a model of skin fibrosis induced by subcutaneous injections of bleomycin. At early time points, bleomycin-induced macrophage infiltration in the dermis and local TGF-β production were similar in Smad3−/− and wild-type mice. In contrast, at day 28, lesional skin from Smad3−/− mice showed attenuated fibrosis, lower synthesis and accumulation of collagen, and reduced collagen gene transcription in situ, compared to wild-type mice. Connective tissue growth factor and α-smooth muscle actin expression in lesional skin were also significantly attenuated. Electron microscopy revealed an absence of small diameter collagen fibrils in the dermis from bleomycin-treated Smad3−/− mice. Compared to fibroblasts derived from wild-type mice, Smad3−/− fibroblasts showed reduced in vitro proliferative and profibrotic responses elicited by TGF-β. Together, these results indicate that ablation of Smad3 is associated with markedly altered fibroblast regulation in vivo and in vitro, and confers partial protection from bleomycin-induced scleroderma in mice. Reduced fibrosis is due to deregulated fibroblast function, as the inflammatory response induced by bleomycin was similar in wild-type and Smad3−/− mice.

Targeted Disruption of TGF-β/Smad3 Signaling Modulates Skin Fibrosis in a Mouse Model of Scleroderma

Platelet-derived growth factor (PDGF) is a polypeptide found in a variety of tissues, including bone, where it could act as an autologous regulator of skeletal remodeling. Therefore, a recombinant B chain homodimer of human PDGF was studied for its effects on bone formation in cultured rat calvariae. PDGF at 10-100 ng/ml stimulated [3H]thymidine incorporation into DNA by up to sixfold and increased the DNA content and the number of colcemid-induced metaphase arrested cells. This effect was observed in the fibroblast and precursor cell-rich periosteum. As a result of its mitogenic actions, PDGF enhanced [3H]proline incorporation into collagen, an effect that was observed primarily in the osteoblast-rich central bone. The effect of PDGF was not specific for collagen since it also increased noncollagen protein synthesis. In addition, PDGF increased bone collagen degradation. PDGF and insulin-like growth factor (IGF) I had additive effects on calvarial DNA synthesis, but PDGF opposed the stimulatory effect of IGF I on collagen synthesis and IGF I prevented the PDGF effect on collagen degradation. In conclusion, PDGF stimulates calvarial DNA synthesis which causes an increased number of collagen-synthesizing cells, but PDGF also enhances bone collagen degradation.

Effects of platelet-derived growth factor on bone formation in vitro.

Study design Cells from normal rabbit nucleus pulposus (NP) and anulus fibrosus (AF) were cultured in alginate beads for as long as 14 days to allow them to reform a matrix made up of two compartments: the cell-associated matrix (CM) and further removed matrix (FRM). At different time points, the CM and FRM made by each cell population were analyzed using histologic, biochemical, and immunologic assays. Objectives To study the metabolism of normal rabbit NP and AF cells in alginate by characterizing the CM and FRM formed by each cell population, and to identify metabolic properties that may shed light on mechanisms at play in disc degeneration. Summary of background data Little is known about the metabolism of intervertebral disc cells, in part because of the lack of microculture systems appropriate for the study of these cells in vitro. In recent studies from our laboratories, it was suggested that articular chondrocytes cultured in alginate beads remain phenotypically stable and reform a matrix similar to the one they populate in vivo. This culture system appears ideally suited for the study of intervertebral cells available only in limited numbers. Methods Rabbit NP and AF cells released from the matrix by sequential enzyme digestion were encapsulated in alginate beads (20,000 cells/bead) and cultured for as long as 14 days. At selected time points, beads were solubilized with calcium chelating agents, and the CM and FRM were isolated. The rate of 35S-sulfate incorporation into proteoglycans, and the contents of various extracellular matrix molecules (total sulfated proteoglycans, antigenic keratan sulfate, hyaluronan, collagen, and pyridinium crosslinks) were measured. Results Both NP and AF cells remained phenotypically stable in the alginate gel throughout the culture period and reestablished a matrix composed of CM and FRM compartments. The two cell populations exhibited numerous differences in their metabolic activities in vitro. Nucleus pulposus cells synthesized fewer proteoglycan and collagen molecules and were less effective in incorporating these into the CM than AF cells. Conclusions Intervertebral disc cells, especially NP cells, are extremely sluggish in reforming a CM, a protective shell rich in proteoglycans and collagen molecules. This may help explain why damage to the NP often is accompanied by progressive degeneration of the disc in vivo.

Metabolism of the extracellular matrix formed by intervertebral disc cells cultured in alginate

The purpose of this study was to evaluate the effect of laser energy at nonablative levels on joint capsular histologic and biochemical properties in an in vitro rabbit model. The medial and lateral portions of the femoropatellar joint capsule from both stifles of 12 mature New Zealand White rabbits were used. Specimens were divided into three treatment groups (5 watts, 10 watts, and 15 watt) and one control group using a randomized block design. Specimens were placed in a 37 degrees bath of lactated Ringer's solution and laser energy was applied using a holmium:yttrium-aluminum-garnet laser in four transverse passes across the tissue at a velocity of 2 mm/sec with the handpiece set 1.5 mm from the synovial surface. Histologic analysis revealed thermal alteration of collagen (fusion) and fibroblasts (pyknosis) at all energy densities, with higher laser energy causing significantly greater morphologic changes over a larger area (P 0.05). This study demonstrated that nonablative laser energy caused significant thermal damage to the joint capsular tissue in an energy-dependent fashion, but type I collagen content and nonreducible crosslinks (P > 0.05). This study demonstrated that nonablative laser energy caused significant thermal damage to the joint capsular tissue in an energy-dependent fashion, but type I Collagen content and nonreducible corsslinks were not significantly altered.

The effect of nonablative laser energy on joint capsular properties. An in vitro histologic and biochemical study using a rabbit model

Determination of hydroxyproline in tissue collagen hydrolysate by derivatization and isocratic reversed-phase high-performance liquid chromatography

Enhanced glucose utilization was observed in continuous cultures of macrophages in medium containing 4mM Quadrol, [N, N, N', N', Tetrakis(2-hydroxypropyl)ethylenediamine]. This enhancement was both time and concentration dependent. Radiolabeled 4mM Quadrol, after incubation with macrophages for 60 minutes, was shown to be associated with the cells at a level of 4 nmoles/106 cells. This association increased linearly with time, reaching a maximum at 60 minutes with no observable difference after 24 hours. Trypsin-EDTA treatment of these macrophages for 15 minutes reduced the amount of Quadrol associated with cells by about 50%, Quadrol, unlike Ca Ionophore A23187, did not induce influx of 45Ca into the cells within the incubation period of 60 minutes. Quadrol methacrylate and Poly(Quadrol methacrylate) stimulated macrophages to exhibit increased phagocytosis of polystyrene beads. This stimulation was comparable to that observed for Quadrol.

Investigation into the mechanism of stimulation of macrophages by Quadrol.

The rate of collagen deposition in implanted polytetrafluoroethylene (PTFE) tubing in non-diabetic and streptozotocin-induced (STZ) diabetic mice was measured during 14 days post-wounding. At the time of implantation, test groups received injections of either Quadrol [N,N,N',N'-tetrakis(2-hydroxypropyl)ethylenediamine], glucan, or buffer in an area adjacent to the wound site. The accumulation of collagen in the implants of Quadrol-treated non-diabetic animals was more than 200% above control on days 8 to 11 and was 50% above control on day 14. In Quadrol-treated STZ-diabetic mice, the collagen accumulation gradually increased from 50% above control on day 8 to 200% above control on day 14. Treatment with glucan increased the collagen accumulation in normal mice 200 to 300% above control from days 8 to 11 respectively and then 30% above control on day 14. Collagen accumulation in the implants of the glucan-treated STZ-diabetic mice was similar to the control group. These results indicate that Quadrol promotes in vivo collagen synthesis and that Quadrol may be effective as a stimulator of wound healing in diabetic and non-diabetic animals.

Promotion of Wound Collagen Formation in Normal and Diabetic Mice by Quadrol

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Determination of hydroxyproline in tissue collagen hydrolysate by derivatization and isocratic reversed-phase high-performance liquid chromatography

Investigation into the mechanism of stimulation of macrophages by Quadrol.

Promotion of Wound Collagen Formation in Normal and Diabetic Mice by Quadrol