tacrolimus and Hypertrophy

Multifocal fibrosclerosis is the term used to represent a combination of similar fibrous lesions occurring at different anatomical sites. We herein report a hypertrophic pachymeningitis patient with a soft tissue mass around the thoracic vertebral bodies. A histopathological analysis of the biopsied tissues from both lesions showed dense fibrosis and a marked infiltration of lymphocytes and plasma cells, which lead to the diagnosis of multifocal fibrosclerosis. This pathological condition closely resembles that of IgG4-related disease and is a very rare combination of manifestations. Our case suggests that hypertrophic pachymeningitis patients need to also undergo a whole body examination.

Topics: Aged; Anti-Inflammatory Agents; Humans; Hypertrophy; Immunosuppressive Agents; Male; Meningitis; Methylprednisolone; Plasma Cells; Retroperitoneal Fibrosis; Tacrolimus; Thoracic Vertebrae; Treatment Outcome

In response to a requirement for increased contractile power in vivo, mammalian cardiac myocytes adapt through a hypertrophic response (cell enlargement in the absence of cell division). This response can be simulated by exposing isolated myocytes in primary culture to alpha-adrenergic agonists or the vasoactive peptide, endothelin-1. The signalling pathways responsible for hypertrophic growth have been actively studied, and it is likely that reversible protein phosphorylation and dephosphorylation are involved. Three signalling pathways show particular potential as regulators of the response, ie protein kinase C (PKC), mitogen-activated protein kinase (MAPK) cascades, and calcineurin. These species are thought to regulate the rate and specificity of gene transcription ultimately through modifying the transactivating activity of nuclear transcription factors. There are three pertinent MAPK cascades, the extracellular signal-regulated kinase (ERK) cascade, the c-Jun N-terminal kinase (JNK or SAPK1) cascade, and the p38-MAPK (SAPK2-5) cascade. PKC participates in the activation of the ERK cascade but does not contribute significantly to the activation of the two remaining cascades. Calcineurin (or protein phosphatase 2B) is activated by increases in [Ca2+i] through the [Ca2+]-sensing protein, calmodulin. In this review, I discuss the evidence for and against the involvement of these signalling proteins in the induction of myocyte hypertrophy and emphasize that the ERK cascade should perhaps feature more widely in the collective consciousness.

Topics: Animals; Calcineurin; Gene Expression Regulation; Humans; Hypertrophy; Mitogen-Activated Protein Kinases; Myocardium; Oxidative Stress; Phosphorylation; Protein Kinase C; Signal Transduction; Tacrolimus

to evaluate the renal toxicity caused by tacrolimus and mycophenolate mofetil (MMF) in a single kidney ischemia and reperfusion model.. experimental study using Wistar rats, submitted to right nephrectomy and left renal ischemia for 20 minutes, separated into groups in the postoperative period (PO): 1) Control (nonoperated); 2) Sham (operated, without PO drug); 3) TAC0.1, TAC1 and TAC10, tacrolimus administered PO at doses of 0.1mg/kg, 1mg/kg and 10mg/kg via gavage, respectively; 4) MMF, administered mycophenolate mofetil 20mg/kg; 5) MMF/TAC1 and MMF/TAC0.5, with an association of mycophenolate mofetil 20mg/kg and tacrolimus 1mg/kg and 0.5mg/kg, respectively. They were killed on the 14th PO and the kidney was removed for tissue oxidative stress analysis, by the dosage of reduced glutathione (GSH), lipoperoxidation (LPO) and protein carbonylation (PCO), and histological analysis by glomerular stereology (Glomerular volume density, Numerical density glomerular and mean glomerular volume). Renal function was evaluated by the measurement of serum creatinine and urea.. both drugs caused alterations in renal function, and the toxicity of tacrolimus was dose-dependent. Subacute toxicity did not show significant glomerular histological changes, and there was renal and compensatory glomerular hypertrophy in all groups except TAC10.. Both drugs cause changes in renal function. Glomerular morphometry and stereology showed negative interference of immunosuppressants during compensatory glomerular hypertrophy.

Topics: Animals; Hypertrophy; Immunosuppressive Agents; Ischemia; Kidney; Mycophenolic Acid; Rats; Rats, Wistar; Reperfusion; Tacrolimus

Osteopontin (OPN), a multifunctional glycophosphoprotein, has been reported to contribute to the development and progression of cardiac remodeling and hypertrophy. Cardiac-specific OPN knockout mice were protected against hypertrophy and fibrosis mediated by Ang II. Recently, transgenic mice expressing the active form of the Na(+)/H(+) exchanger isoform 1 (NHE1) developed spontaneous hypertrophy in association with elevated levels of OPN. The mechanism by which active NHE1 induces OPN expression and contributes to the hypertrophic response remains unclear. To validate whether expression of the active form of NHE1 induces OPN, cardiomyocytes were stimulated with Ang II, a known inducer of both OPN and NHE1. Ang II induced hypertrophy and increased OPN protein expression (151.6 ± 28.19 %, P < 0.01) and NHE1 activity in H9c2 cardiomyoblasts. Ang II-induced hypertrophy and OPN protein expression were regressed in the presence of an NHE1 inhibitor, EMD 87580, or a calcineurin inhibitor, FK506. In addition, our results indicated that activation of NHE1-induced NFAT3 translocation into the nucleus and a significant activation of the transcription factor Gata4 (NHE1: 149 ± 28 % of control, P < 0.05). NHE1-induced activation of Gata4 was inhibited by FK506. In summary, our results suggest that activation of NHE1 induces hypertrophy through the activation of NFAT3/Gata4 and OPN expression.

Topics: Animals; Cation Transport Proteins; GATA4 Transcription Factor; Gene Expression Regulation; Hypertrophy; Mice; Mice, Knockout; Myoblasts; Myocytes, Cardiac; NFATC Transcription Factors; Osteopontin; Sodium-Hydrogen Exchanger 1; Sodium-Hydrogen Exchangers; Tacrolimus

Topics: Child, Preschool; Cyclosporine; Drug Substitution; Humans; Hypertrophy; Immunosuppressive Agents; Lip; Lip Diseases; Male; Nephrotic Syndrome; Remission Induction; Tacrolimus; Treatment Outcome

A 75-year-old man developed hearing loss and hoarseness; 5 months later, he suffered from headache and loss of appetite. A blood test showed an inflammatory reaction, a high level of serum IgG4 (254.0 mg/dl), and positive reaction for MPO-ANCA. Gadolinium enhanced T1 weighted head magnetic resonance imaging (MRI) revealed dural thickening with marked enhancement. Infiltration of lymphocytes and anti-IgG4-positive plasma cells were detected in the dura mater by meningeal biopsy; thus, he was diagnosed with MPO-ANCA-positive IgG4-related hypertrophic pachymeningitis. His clinical manifestations, and serologic and MRI findings improved with steroid treatment; however, they recurred during steroid tapering and he presented with right orbital apex syndrome. We then added an immunosuppressive drug to his regimen. It was difficult to reduce the symptoms of this case, with oral steroid monotherapy, and its combination with an immunosuppressive drug was necessary.

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Humans; Hypertrophy; Immunoglobulin G; Immunosuppressive Agents; Male; Meningitis; Methylprednisolone; Orbital Diseases; Peroxidase; Recurrence; Tacrolimus

Keloids and hypertrophic scars (HSc) affect 4.5-16% of the population. Thus far, the different approaches of keloid treatment are not very efficient, with a 50% relapse rate and many ongoing researches are looking for simple, safe and more efficient therapeutic methods. Tacrolimus is an immunomodulator that could be useful in treating keloid.. The objective of this study is to evaluate the effectiveness of Tacrolimus in inhibiting HSc formation on rabbits' ears model and to check optical skin spectroscopy in tissue characterization.. Our study was carried out on 20 New-Zealand female white rabbits. HSc were obtained by wounding rabbits' ear. These wounds were treated with intradermal injections of tacrolimus (0.2-0.5 mg/cm(2)) or a vehicule. The assessment of treatment efficacy was performed by clinical examinations, histological assay and skin spectrometry.. Tacrolimus did not induce general or local side-effects. The scar elevation index in treated subjects was half less than that of the untreated ones. Furthermore, dermal thickness and inflammatory cellular density were both significantly smaller for treated scars than for the control ones. In vivo optical skin spectroscopy can characterize hypertrophic and normal skin with high sensibility and specificity.. Intradermal injection of tacrolimus at 0.5 mg/cm(2) is an efficient way to prevent HSc in our experiment model and its tolerance is correct. Optical spectroscopy could be a good non-invasive tool to evaluate HSc treatment. These promising results might be proposed for patients suffering from keloid.

Topics: Animals; Cicatrix, Hypertrophic; Dermoscopy; Disease Models, Animal; Ear, External; Female; Hypertrophy; Immunosuppressive Agents; Injections, Intradermal; Keloid; Rabbits; Spectrum Analysis; Tacrolimus; Wounds and Injuries

Bladder outlet obstruction (BOO) leads to compensatory bladder hypertrophy. However, the hypertrophy mechanism remains elusive. We report that calcineurin (Cn) is involved in bladder hypertrophy.. Partial BOO was surgically induced in 10-week-old female Wistar rats. The bladder was excised 2, 4 and 6 weeks following surgery in 9 rats each. Histological study was performed at each time point. Cn expression was examined by Western blot analysis. Myosin heavy chain expression was evaluated on gels stained with Coomassie blue. Primary cultured bladder smooth muscle cells were infected with recombinant adenoviruses encoding a constitutive active form of CnA (DeltaCnA), CnB and lacZ, and cell size was measured.. In histological findings bladder smooth muscle hypertrophy was observed 2 and 4 weeks after surgery. However, the thickened muscles became thinner 6 weeks after BOO. CnA expression 2 weeks after BOO increased 3.2-fold compared with that of controls. Expression significantly decreased 4 and 6 weeks after surgery. In contrast, CnB expression was unchanged throughout hypertrophy development. Changes in myosin heavy chain expression correlated with changes in CnA. We observed significant hypertrophy in DeltaCnA and CnB over expressing smooth muscle cells. Moreover, FK506, which is a potent inhibitor of Cn, blocked hypertrophy in DeltaCnA and CnB over expressing smooth muscle cells.. These data suggest that Cn has an important role in the induction of bladder smooth muscle hypertrophy.

Topics: Animals; Blotting, Western; Calcineurin; Calcineurin Inhibitors; Cell Size; Female; Hypertrophy; Immunoenzyme Techniques; Muscle, Smooth; Myosin Heavy Chains; Myosins; Rats; Rats, Wistar; Tacrolimus; Urinary Bladder Neck Obstruction

Topics: Animals; Calcineurin; Cyclosporine; Hypertrophy; Mice; Muscle, Skeletal; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Rats; Tacrolimus

Molecular signaling pathways linking increases in skeletal muscle usage to alterations in muscle size have not been identified. In the present study, we tested the hypothesis that calcineurin, a calcium-regulated phosphatase recently implicated in the signaling of some forms of cardiomyopathic growth, is required to induce skeletal muscle hypertrophy and muscle fiber type conversions associated with functional overload in vivo. Administration of the specific calcineurin inhibitors cyclosporin (CsA) or FK506 to mice, for which the fast plantaris muscle was overloaded for 1-4 weeks, prevented the rapid doubling of mass and individual fiber size and the 4-20-fold increase in the number of slow fibers that characterize this condition. CsA treatment influenced the expression of muscle myofibrillar protein genes in a way reflective of fiber phenotype transformations but only in the long term of the overload condition, suggesting that the control of this growth response by calcineurin is not limited to the transcriptional activation of these muscle-specific genes. Clinically, these results provide insight to the post-surgical muscle wasting and weakness observed in recovering transplant recipients administered therapeutic dosages of these immunosuppressants.

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Cyclosporine; Gene Expression Regulation; Hindlimb; Hypertrophy; Major Histocompatibility Complex; Male; Mice; Muscle Fibers, Fast-Twitch; Muscle Fibers, Slow-Twitch; Muscle, Skeletal; Myofibrils; Protein Isoforms; Signal Transduction; Tacrolimus; Transcription, Genetic; Troponin I; Weight-Bearing

Topics: Animals; Digestive System; Dogs; Female; Heart; Hypertrophy; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Myocardium; Necrosis; Polyenes; Sirolimus; Tacrolimus; Transplantation, Homologous