tetracycline and Fibrosis

Pleurodesis is a frequently preferred procedure in thoracic surgery, and many factors may affect the process. We aimed to determine whether the administration of systemic diclofenac sodium diminishes the effectiveness of the pleurodesis induced by intrapleural tetracycline in rabbits.. Twelve male New Zealand rabbits that received tetracycline 35 mg/kg intrapleurally were allocated into two groups. The first group (diclofenac group, n = 6) received 2 mg/kg diclofenac sodium intramuscularly for 10 days, and the second group (control group, n = 6) received acetaminophen 30 mg/kg orally for 10 days after the pleurodesis procedure. The rabbits were sacrificed after 28 days, and the pleural spaces were assessed grossly for evidence of pleurodesis and microscopically for evidence of fibrosis, inflammation, and collagenization.. The mean macroscopic pleurodesis score of the diclofenac group was 2.16 +/- 0.40 compared with 2.83 +/- 0.40 in the control group (p = .027). The mean microscopic pleurodesis score of the diclofenac group was 2. 3 +/- 1.03, whereas it was 3.5 +/- 0.54 in the control group (p = .045).. The administration of diclofenac sodium for 10 days following tetracycline pleurodesis reduces the effectiveness of pleurodesis in rabbits.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Diclofenac; Disease Models, Animal; Fibrosis; Male; Pleura; Pleurodesis; Rabbits; Sclerosing Solutions; Tetracycline

In this study, we developed a double-transgenic mouse model allowing hepatocyte-specific and regulated expression of the redox-modifying enzymes copper/zinc superoxide dismutase (SOD) and glutathione peroxidase (GPX) by using a tetracycline-regulatable gene expression system. Within this system, the SOD and GPX level can be regulated deliberately by addition or removal of doxycycline hydrochloride to the drinking water. As reactive oxygen species (ROS) have been implicated in a number of pathological conditions, such as atherosclerosis, thrombosis, or liver fibrosis, processes that are also frequently associated with enhanced levels of plasminogen activator inhibitor-1 (PAI-1), it was the aim of the present study to investigate the influence of SOD and GPX overexpression on the regulation of PAI-1. PAI-1 mRNA and protein levels in tetracycline transactivator-dependent SOD-overexpressing double-transgenic mice reached values 2.5- to threefold above the normal mRNA level. By applying doxycycline, a deinduction of the PAI-1 levels was observed. By using the same protocol, PAI-1 mRNA and protein levels were enhanced in GPX double-transgenic mice, and again this response was blunted by the addition of doxycycline. These studies provide some new information regarding the role of ROS within the proteolytic processes in hepatocytes that require PAI-1.

Topics: Animals; Fibrosis; Gene Expression Regulation; Glutathione Peroxidase; Hepatocytes; Mice; Mice, Transgenic; Plasminogen Activator Inhibitor 1; Protein Synthesis Inhibitors; Reactive Oxygen Species; RNA, Messenger; Superoxide Dismutase; Tetracycline

Idiopathic dilated cardiomyopathy (DCM), ventricular systolic dysfunction and chamber dilatation are accompanied by architectural remodeling, wall thinning and cardiac myocyte slippage. Recent work has demonstrated an association between collagen degradation and an increased expression of matrix metalloproteinases (MMPs). Accordingly, we have sought to correlate (a) collagen degradation with MMP elevations and, (b) assay the neutralizing potential of a known inhibitor of MMP, tetracycline on MMPs in DCM.. Assessment of LV volume and shape by 2-D echocardiography was performed. Light microscopic assessment of histopathology in picrosirius red stained biopsy samples of 11 DCM patients and six post-transplant patients was performed. Zymographic estimation of MMP activity and influence of tetracycline on MMP activity was assessed.. Small amount of interstitial collagen was noted in the control group, whereas in the DCM hearts, chamber dilatation was associated with areas of scanty myocyte necrosis, islands of excess collagen, and focal areas of absent or scanty collagen with intact myocytes. In cardiomyopathic tissue, collagenase activity was markedly elevated at 63% compared with 8% in post-transplant tissue. Tetracycline at a concentration of 285+/-10 microM (IC50) inhibited collagenase activity by 50% in cardiomyopathic tissue.. Areas of focal interstitial collagen accumulation were accompanied by collagen fiber lysis and increased collagenase activity in dilated cardiomyopathy. This enhanced collagenolytic activity found in endomyocardial biopsy tissue was inhibited by tetracycline. The non-antibiotic property of tetracycline may be of potential value in the prevention of ventricular dilatation in idiopathic dilated cardiomyopathy.

Topics: Adult; Biomarkers; Cardiomyopathy, Dilated; Collagen; Collagenases; Echocardiography; Electrophoresis, Polyacrylamide Gel; Female; Fibrosis; Heart Diseases; Heart Transplantation; Humans; Inhibitory Concentration 50; Male; Matrix Metalloproteinases; Middle Aged; Myocardium; Necrosis; Tetracycline; Time Factors

Mucosal changes have been well described in chronic sinusitis, yet little is known about the underlying bone, despite clinical and experimental evidence suggesting that bone may be involved in chronic sinusitis. Techniques of undecalcified bone analysis were used for detailed histologic examination of ethmoid bone in chronic sinusitis compared with controls. Bone synthesis, resorption, and inflammatory cell presence were specifically assessed. Additionally, histomorphometry techniques were used to determine ethmoid bone physiology in individuals undergoing surgery for chronic sinusitis. Overall, individuals undergoing surgery for chronic sinusitis were found to have evidence of marked acceleration in bone physiology with histologic changes including new bone formation, fibrosis, and presence of inflammatory cells. These findings are compared with osteomyelitis in long bone and the jaw. The suggestion that underlying bone may serve as a catalyst for chronic sinusitis is supported and implications for therapy are discussed.

Topics: Adult; Anti-Bacterial Agents; Antibiotic Prophylaxis; Bone Remodeling; Bone Resorption; Chronic Disease; Coloring Agents; Demeclocycline; Edema; Endoscopy; Ethmoid Bone; Ethmoid Sinusitis; Female; Fibrosis; Humans; Male; Mandibular Diseases; Mucous Membrane; Osteitis; Osteogenesis; Osteomyelitis; Prospective Studies; Rhinitis; Single-Blind Method; Tetracycline; Turbinates

Bleomycin is the antineoplastic agent used most commonly for the treatment of malignant pleural effusion. It is absorbed rapidly from the pleural space and does not elicit pleurodesis in the normal rabbit pleura. Mitoxantrone is a new antineoplastic that differs from bleomycin in that it binds to membranes. Accordingly it might remain in the pleural space for a longer period and produce a pleurodesis. The objective of this project was to determine whether mitoxantrone is an effective sclerosant in an experimental model in rabbits. The following medications were instilled intrapleurally in anesthetized male rabbits: 35 mg/kg tetracycline or 0.5, 1.0, or 2.0 mg/kg mitoxantrone. The animals were killed at 28 days and the pleural spaces assessed grossly for pleurodesis and microscopically for fibrosis and inflammation. The mean degree of gross pleurodesis did not differ significantly in the rabbits that received tetracycline (3.8 +/- 0.4) and in the rabbits that received 2 mg/kg mitoxantrone (3.2 +/- 1.3). The degree of pleural and lung inflammation was significantly greater after mitoxantrone than after tetracycline, both ipsilaterally and contralaterally. The mortality after the highest dose of mitoxantrone was 50%. From this study we conclude that the intrapleural administration of mitoxantrone in rabbits can produce a pleurodesis. The histologic picture after mitoxantrone administration differs markedly from that after tetracycline injection. After mitoxantrone injection there are many more inflammatory cells present on the side that received the injection, and there is much more fibrosis and inflammation in the contralateral pleura and lung. The model of pleural fibrosis following intrapleural mitoxantrone may be useful for the study of pleural fibrosis.

Topics: Animals; Antineoplastic Agents; Dose-Response Relationship, Drug; Fibrosis; Lethal Dose 50; Male; Mitoxantrone; Pleura; Pleurodesis; Protein Synthesis Inhibitors; Rabbits; Sclerosing Solutions; Tetracycline

The ideal agent to produce pleurodesis has not been identified. Tetracycline, the drug used most commonly in the 1980s, is no longer available. Talc either aerosolized or in a slurry is the agent used just most commonly at the present time, but there are concerns about its safety. Another possibility is silver nitrate, which was widely used in the past, but was abandoned on account of side effects. We hypothesized that lower concentrations of silver nitrate than had been used in the past would be effective in creating a pleurodesis in rabbits. The following medications in a total volume of 2 mL were instilled intrapleurally in three groups of ten anesthetized rabbits: 0.25% or 0.50% silver nitrate and 35 mg/kg tetracycline. Twenty-eight days after the injection, the animals were sacrificed and the pleural spaces were assessed grossly for evidence of pleurodesis and microscopically for evidence of fibrosis and inflammation. The intrapleural injection of 0.50% silver nitrate produced an effective pleurodesis. The mean degree of gross pleurodesis in the rabbits that received 0.50% silver nitrate (3.4 +/- 1.2) did not differ significantly from that of the rabbits that received tetracycline (3.5 +/- 0.7) (scale 0 to 4). The mean degree of microscopic pleural fibrosis in the rabbits that received 0.50% silver nitrate (3.4 +/- 0.7) did not differ significantly from that of the rabbits that received tetracycline (3.9 +/- 0.3). However, 0.25% silver nitrate was ineffective in creating pleural fibrosis, either grossly or microscopically. No rabbits died after the intrapleural injection of the drugs. There were no observed side effects after the injection of silver nitrate. The present study demonstrates that 0.50% silver nitrate instilled into the pleural space is an effective agent for producing pleurodesis in the rabbit; its effect is comparable to tetracycline 35 mg/kg. This agent should be compared with tetracycline derivatives and talc in studies in humans.

Topics: Analysis of Variance; Animals; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Fibrosis; Lung; Pleura; Pleurisy; Pleurodesis; Rabbits; Sclerosing Solutions; Silver Nitrate; Statistics, Nonparametric; Tetracycline

Topics: Bleomycin; Drainage; Fibrosis; Humans; Pleural Diseases; Pleural Effusion, Malignant; Sclerosing Solutions; Tetracycline; Tissue Adhesions

The two agents most commonly used for producing a pleurodesis are tetracycline and bleomycin. Tetracycline is no longer available due to more stringent requirements on the manufacturing process. The objective of this project was to determine whether bleomycin is an effective sclerosant in an experimental model in rabbits. The following medications were instilled intrapleurally in anesthetized male rabbits: tetracycline, 35 mg/kg, or bleomycin, 1.5 or 3.0 IU/kg diluted to a total volume of 1 ml with bacteriostatic saline solution. Twenty-eight days after the instillation, the animals were killed, and the pleural spaces were assessed grossly for evidence of pleurodesis and microscopically for evidence of fibrosis and inflammation. The intrapleural injection of bleomycin was ineffective in creating pleural fibrosis, either grossly or microscopically. The mean degree of gross pleurodesis in the six rabbits who received tetracycline was 2.7 +/- 1.5 (scale 0 to 4), while that in the rabbits who received the highest dose of bleomycin was 0.0 +/- 0.0. Based on this study, we recommend that bleomycin not be used as a pleural sclerosant in patients with nonneoplastic pleural disease, eg, those with pneumothorax, congestive heart failure or cirrhosis, and pleural effusion.

Topics: Analysis of Variance; Animals; Bleomycin; Drug Evaluation, Preclinical; Fibrosis; Male; Pleura; Pleurisy; Rabbits; Sclerosing Solutions; Tetracycline; Time Factors