sirolimus and Pulmonary-Fibrosis

In pulmonary fibrosis, autophagy handles the maintenance of alveolar epithelial cells, prevents epithelial-mesenchymal transition (EMT), and controls collagen turnover. The mammalian target of rapamycin (mTOR) and its translational-dependent proteins are essential regulators of autophagy. Irbesartan (IRB) has earlier ameliorative effects in experimental pulmonary fibrosis. The current study aimed to explore therapeutic autophagy-modulated pulmonary fibrotic changes by IRB versus rapamycin (RAPA) in bleomycin (BLM)-challenged rats.. A single intratracheal BLM dose at day (0), IRB in different doses (10, 20, and 40 mg/kg) or RAPA (2.5 mg/kg) was given daily for 14 continuous days.. IRB significantly diminished the fibrotic lung scores. Pulmonary levels of transforming growth factor (TGF)-β1 and hydroxyproline exhibited marked attenuation in IRB (40 mg/kg)-treated rats compared to other treated groups. IRB (40 mg/kg) was not significantly different from RAPA. It downregulated the fibrotic lung phosphorylated mammalian target of rapamycin (p-mTOR) levels and augmented lung Unc-51-like autophagy activating kinase 1 (ULK1), LC3-I and LC3-II more than IRB (10 and 20 mg/kg)-treated fibrotic groups.. Autophagic effects via the mTOR signalling pathway may play a role in IRB's antifibrotic effects. Consideration of IRB as a therapeutic antifibrotic agent in pulmonary fibrosis needs further experimental and clinical long-term validation, especially in comorbid with primary hypertension, heart failure, and diabetic renal insults.

Topics: Animals; Autophagy; Bleomycin; Epithelial-Mesenchymal Transition; Irbesartan; Mammals; Pulmonary Fibrosis; Rats; Sirolimus; TOR Serine-Threonine Kinases; Transforming Growth Factor beta1

Epithelial-mesenchymal transition (EMT) plays a pivotal role in idiopathic pulmonary fibrosis (IPF). In bleomycin-induced pulmonary fibrosis mice, we observed that inhibition of mTOR (mammalia target of rapamycin) attenuated IPF. Rapamycin suppressed the down-regulation of E-cadherin and up-regulation of fibronectin in bleomycin-induced pulmonary fibrosis mice. In addition, dual immunofluorescence staining for E-cadherin and fibronectin demonstrated that rapamycin pretreatment decreased the proportions of AECs undergoing EMT in bleomycin-induced pulmonary fibrosis, indicating that mTOR inhibition suppressed EMT in vivo. In the setting of transforming growth factor (TGF)-β1-induced EMT in AECs, we found that mTOR inhibitor attenuated TGF-β1-induced EMT in AECs. This EMT was characterized by morphology and cell skeleton changes and the expression of EMT phenotype markers. Finally, mTOR blockade decreased S6k and TGF-β1-induced Smad2/3 phosphorylation. Bleomycin induced pulmonary fibrosis and EMT in mice, while mTOR repression inhibited bleomycin-induced pulmonary fibrosis and attenuated EMT in vivo. Hence, our study provided evidence of a novel mechanism by which mTOR inhibitor ameliorates pulmonary fibrosis. Suppression of mTOR and EMT may be a target for treatment of pulmonary fibrosis.

Topics: Animals; Bleomycin; Cadherins; Disease Models, Animal; Epithelial Cells; Epithelial-Mesenchymal Transition; Fibronectins; Gene Expression Regulation; Male; Mice; Phosphorylation; Pulmonary Alveoli; Pulmonary Fibrosis; Ribosomal Protein S6 Kinases, 90-kDa; Signal Transduction; Sirolimus; Smad2 Protein; Smad3 Protein; TOR Serine-Threonine Kinases; Transforming Growth Factor beta1

Paraquat (PQ) is a widely used herbicide indeveloping countries worldwide, and pulmonary fibrosis is one of the most typical features of PQ poisoning. The molecular mechanism of PQ toxicity especially how to treat PQ-induced pulmonary fibrosis is still largely unknown. In animal model of pulmonary fibrosis, we used HE staining, western blotting assay and Real-time PCR assay to analyze the effects of rapamycin on the PQ-induced epithelial mesenchymal transition (EMT). We found that PQ induced the pulmonary fibrosis using HE staining and Masson's staining, and up-regulated the activity of HYP and the mRNA expressions of Collagen I and III (COL-1and COL-3) in pulmonary tissues. We also found that rapamycin down-regulated the mesenchymal cell marker Vimentin and up-regulated the epithelial cell marker E-cadherin both in mRNA and protein levels compared with PQ group. And the EMT associated transcription factor Snail was decreased by rapamycin treatment compared with PQ group. And PQ decreased the Nrf2 expression both in mRNA and protein levels, and rapamycin inhibited these effects of PQ. SFN, a activator of Nrf2, could inhibit the EMT and the expression of Snail. And knockdowon of Nrf2 could abolish the inhibitory effects of rapamycin of PQ-induced EMT. In conclusion, rapamycin protects against paraquat-induced pulmonary fibrosis by activation of Nrf2 signaling pathway.

Topics: Animals; Epithelial-Mesenchymal Transition; Herbicides; Lung; Male; NF-E2-Related Factor 2; Paraquat; Protective Agents; Pulmonary Fibrosis; Rats; Signal Transduction; Sirolimus

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Cell Movement; Cell Proliferation; Humans; Macrophages; Macrophages, Alveolar; Mice; Mice, Knockout; Proto-Oncogene Proteins; Pulmonary Fibrosis; Silicon Dioxide; Silicosis; Sirolimus; U937 Cells

The p70 ribosomal S6 kinase (S6K) is a downstream substrate that is phosphorylated and activated by the mammalian target of rapamycin complex and regulates multiple cellular processes associated with fibrogenesis. Recent studies demonstrate that aberrant mTORC1-S6K signaling contributes to various pathological conditions, but a direct role in pulmonary fibroproliferation has not been established. Increased phosphorylation of the S6K pathway is detected immediately following transforming growth factor-α (TGF-α) expression in a transgenic model of progressive lung fibrosis. To test the hypothesis that the S6K directly regulates pulmonary fibroproliferative disease we determined the cellular sites of S6K phosphorylation during the induction of fibrosis in the TGF-α model and tested the efficacy of specific pharmacological inhibition of the S6K pathway to prevent and reverse fibrotic disease. Following TGF-α expression increased phosphorylation of the S6K was detected in the airway and alveolar epithelium and the mesenchyme of advanced subpleural fibrotic regions. Specific inhibition of the S6K with the small molecule inhibitor LY-2584702 decreased TGF-α and platelet-derived growth factor-β-induced proliferation of lung fibroblasts in vitro. Administration of S6K inhibitors to TGF-α mice prevented the development of extensive subpleural fibrosis and alterations in lung mechanics, and attenuated the increase in total lung hydroxyproline. S6K inhibition after fibrosis was established attenuated the progression of subpleural fibrosis. Together these studies demonstrate targeting the S6K pathway selectively modifies the progression of pulmonary fibrosis in the subpleural compartment of the lung.

Topics: Animals; Lung; Mice, Transgenic; Phosphorylation; Platelet-Derived Growth Factor; Pulmonary Fibrosis; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Transforming Growth Factor alpha

Fibrotic diseases display mesenchymal cell (MC) activation with pathologic deposition of matrix proteins such as collagen. Here we investigate the role of mTOR complex 1 (mTORC1) and mTORC2 in regulating MC collagen expression, a hallmark of fibrotic disease. Relative to normal MCs (non-Fib MCs), MCs derived from fibrotic human lung allografts (Fib-MCs) demonstrated increased phosphoinositide-3kinase (PI3K) dependent activation of both mTORC1 and mTORC2, as measured by increased phosphorylation of S6K1 and 4E-BP1 (mTORC1 substrates) and AKT (an mTORC2 substrate). Dual ATP-competitive TORC1/2 inhibitor AZD8055, in contrast to allosteric mTORC1-specific inhibitor rapamycin, strongly inhibited 4E-BP1 phosphorylation and collagen I expression in Fib-MCs. In non-Fib MCs, increased mTORC1 signaling was shown to augment collagen I expression. mTORC1/4E-BP1 pathway was identified as an important driver of collagen I expression in Fib-MCs in experiments utilizing raptor gene silencing and overexpression of dominant-inhibitory 4E-BP1. Furthermore, siRNA-mediated knockdown of rictor, an mTORC2 partner protein, reduced mTORC1 substrate phosphorylation and collagen expression in Fib-, but not non-Fib MCs, revealing a dependence of mTORC1 signaling on mTORC2 function in activated MCs. Together these studies suggest a novel paradigm where fibrotic activation in MCs increases PI3K dependent mTORC1 and mTORC2 signaling and leads to increased collagen I expression via the mTORC1-dependent 4E-BP1/eIF4E pathway. These data provide rationale for targeting specific components of mTORC pathways in fibrotic states and underscore the need to further delineate mTORC2 signaling in activated cell states.

Topics: Cells, Cultured; Collagen Type I; Humans; Lung; Lung Transplantation; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Morpholines; Multiprotein Complexes; Pulmonary Fibrosis; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Ingestion of paraquat (PQ), a widely used herbicide, can cause severe toxicity in humans, leading to a poor survival rate and prognosis. One of the main causes of death by PQ is PQ-induced pulmonary fibrosis, for which there are no effective therapies. The aim of this study was to evaluate the effects of rapamycin (RAPA) on inhibiting PQ-induced pulmonary fibrosis in mice and to explore its possible mechanisms.. Male C57BL/6J mice were exposed to either saline (control group) or PQ (10 mg/kg body weight, intraperitoneally; test group). The test group was divided into four subgroups: a PQ group (PQ-exposed, non-treated), a PQ+RAPA group (PQ-exposed, treated with RAPA at 1 mg/kg intragastrically), a PQ+MP group (PQ-exposed, treated with methylprednisolone (MP) at 30 mg/kg intraperitoneally), and a PQ+MP+RAPA group (PQ-exposed, treated with MP at 30 mg/kg intraperitoneally and with RAPA at 1 mg/kg intragastrically). The survival rate and body weight of all the mice were recorded every day. Three mice in each group were sacrificed at 14 d and the rest at 28 d after intoxication. Lung tissues were excised and stained with hematoxylin-eosin (H&E) and Masson's trichrome stain for histopathological analysis. The hydroxyproline (HYP) content in lung tissues was detected using an enzyme-linked immunosorbent assay (ELISA) kit. The expression of transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) in lung tissues was detected by immunohistochemical staining and Western blotting.. A mice model of PQ-induced pulmonary fibrosis was established. Histological examination of lung tissues showed that RAPA treatment moderated the pathological changes of pulmonary fibrosis, including alveolar collapse and interstitial collagen deposition. HYP content in lung tissues increased soon after PQ intoxication but had decreased significantly by the 28th day after RAPA treatment. Immunohistochemical staining and Western blotting showed that RAPA treatment significantly down-regulated the enhanced levels of TGF-β1 and α-SMA in lung tissues caused by PQ exposure. However, RAPA treatment alone could not significantly ameliorate the lower survival rate and weight loss of treated mice. MP treatment enhanced the survival rate, but had no significant effects on attenuating PQ-induced pulmonary fibrosis or reducing the expression of TGF-β1 and α-SMA.. This study demonstrates that RAPA treatment effectively suppresses PQ-induced alveolar collapse and collagen deposition in lung tissues through reducing the expression of TGF-β1 and α-SMA. Thus, RAPA has potential value in the treatment of PQ-induced pulmonary fibrosis.

Topics: Actins; Animals; Body Weight; Collagen; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Herbicides; Immunohistochemistry; Immunosuppressive Agents; Lung; Male; Methylprednisolone; Mice; Mice, Inbred C57BL; Paraquat; Prognosis; Pulmonary Fibrosis; Sirolimus; Transforming Growth Factor beta1; Treatment Outcome

Idiopathic pulmonary fibrosis (IPF) is the most common and devastating form of interstitial lung disease (ILD) in the clinic. There is no effective therapy except for lung transplantation. Rapamycin is an immunosuppressive drug with potent antifibrotic activity. The purpose of this study was to examine the effects of rapamycin on bleomycin-induced pulmonary fibrosis in rats and the relation to the expression of metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1).. Sprague-Dawley rats were treated with intratracheal injection of 0.3 ml of bleomycin (5 mg/kg) in sterile 0.9% saline to make the pulmonary fibrosis model. Rapamycin was given at a dose of 0.5 mg/kg per gavage, beginning one day before bleomycin instillation and once daily until animal sacrifice. Ten rats in each group were sacrificed at 3, 7, 14, 28 and 56 days after bleomycin administration. Alveolitis and pulmonary fibrosis were semi-quantitatively assessed after HE staining and Masson staining under an Olympus BX40 microscope with an IDA-2000 Image Analysis System. Type I and III collagen fibers were identified by Picro-sirius-polarization. Hydroxyproline content in lung tissue was quantified by a colorimetric-based spectrophotometric assay, MMP-9 and TIMP-1 were detected by immunohistochemistry and by realtime quantitative reverse transcriptase polymerase chain reaction (RT-PCR).. Bleomycin induced alveolitis and pulmonary fibrosis of rats was inhibited by rapamycin. Significant inhibition of alveolitis and hydroxyproline product were demonstrated when daily administration of rapamycin lasted for at least 14 days. The inhibitory efficacy on pulmonary fibrosis was unremarkable until rapamycin treatment lasted for at least 28 days (P < 0.05). It was also demonstrated that rapamycin treatment reduced the expression of MMP-9 and TIMP-1 in lung tissue that was increased by bleomycin.. These results highlight the significance of rapamycin in alleviating alveolitis and pulmonary fibrosis, which is associated with decreased expression of MMP-9 and TIMP-1.

Topics: Animals; Bleomycin; Lung; Male; Matrix Metalloproteinase 9; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; Sirolimus; Tissue Inhibitor of Metalloproteinase-1

The present study was designed to determine whether rapamycin could inhibit transforming growth factor β1 (TGF-β1)-induced fibrogenesis in primary lung fibroblasts, and whether the effect of inhibition would occur through the mammalian target of rapamycin (mTOR) and its downstream p70S6K pathway.. Primary normal human lung fibroblasts were obtained from histological normal lung tissue of 3 patients with primary spontaneous pneumothorax. Growth arrested, synchronized fibroblasts were treated with TGF-β1 (10 ng/mL) and different concentrations of rapamycin (0.01, 0.1, 1, 10 ng/mL) for 24 h. We assessed m-TOR, p-mTOR, S6K1, p-S6K1 by Western blot analysis, detected type III collagen and fibronectin secreting by ELISA assay, and determined type III collagen and fibronectin mRNA levels by real-time PCR assay.. Rapamycin significantly reduced TGF-β1-induced type III collagen and fibronectin levels, as well as type III collagen and fibronectin mRNA levels. Furthermore, we also found that TGF-β1-induced mTOR and p70S6K phosphorylation were significantly down-regulated by rapamycin. The mTOR/p70S6K pathway was activated through the TGF-β1-mediated fibrogenic response in primary human lung fibroblasts.. These results indicate that rapamycin effectively suppresses TGF-β1-induced type III collagen and fibronectin levels in primary human lung fibroblasts partly through the mTOR/p70S6K pathway. Rapamycin has a potential value in the treatment of pulmonary fibrosis.

Topics: Cells, Cultured; Collagen Type III; Fibroblasts; Fibronectins; Humans; Lung; Pulmonary Fibrosis; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transforming Growth Factor beta1

Topics: Animals; Bleomycin; Disease Models, Animal; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Lymphangioleiomyomatosis; Mesenchymal Stem Cell Transplantation; Pulmonary Fibrosis; Sirolimus

Pulmonary fibrosis is a devastating disease with a poor prognosis. Although the diagnosis and pathophysiology of this disease have been better characterized over the past few years, there is no effective therapy for the disease. The aim of this study was to evaluate the anti-inflammatory and anti-fibrotic effects of sirolimus (SRL), which is a potential anti-fibrotic agent, by using bleomycin (BLM)-induced pulmonary fibrosis model in rats.. A single intra-tracheal injection of BLM (2.5 U/kg) was administered and sirolimus (2.5 mg/kg/day) was given orally, beginning either one day before (early SRL) or nine days after (late SRL) the BLM administration. The effect of SRL on fibrosis was studied by analysis of cytokine levels in BAL fluid, measurement of lung tissue hydroxyproline (HPL) content and histopathological examination.. Both early and late SRL administrations caused a decrease in the levels of IL-13, PDGF-A and TGF-β1 (p=0.001) and an increase in IFN-γ levels (p=0.001) in BAL fluid. Early and late SRL also caused a decrease in HPL content (p=0.001). Early sirolimus caused a significant decrease in fibrosis score (p=0.001), while late SRL did not.. Sirolimus was effective in BLM-induced pulmonary fibrosis model, especially in the early phases of the disease.

Topics: Animals; Anti-Inflammatory Agents; Bleomycin; Disease Models, Animal; Injections, Intravenous; Interferon-gamma; Interleukin-13; Lung; Male; Platelet-Derived Growth Factor; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; Sirolimus; Transforming Growth Factor beta1

Ingestion of large quantities of paraquat leads to irreversible, often fatal pulmonary fibrosis. Case presentation. A 50-year-old man (body weight of 78.6 kg) ingested 500 mL Gramoxone containing 200 g/L of paraquat in a suicide attempt. The patient did not seek medical attention until 15 h after ingestion. Initial treatment consisted of the administration of intravenous methylprednisolone, 250 mg once daily. Seventy-two hours after ingestion the patient was transferred to our tertiary care center. Paraquat concentration was 0.2 mg/L in the serum and urinary concentration was 4.42 mg/L. Antioxidative therapy including the administration of acetylcysteine and an anti-inflammatory therapy employing methylprednisolone (1 g/day) was started. Extended daily dialysis was initiated. As the high plasma concentration of paraquat indicated a 100% predicted mortality, we expanded treatment strategies by using the antiproliferative agent rapamycin. A dose of 8 mg/day was started 72 h after the intoxication. Maximum rapamycin concentrations amounted to 12.9 microg/L. Despite these efforts, the patient died on day 18 after intoxication from respiratory failure caused by severe pulmonary fibrosis.. Despite theoretical considerations suggesting the use of rapamycin in paraquat poisoning, the substance failed to halt the progression of pulmonary fibrosis in this case.

Topics: Anti-Inflammatory Agents; Antioxidants; Dialysis; Fatal Outcome; Herbicides; Humans; Intracellular Signaling Peptides and Proteins; Male; Methylprednisolone; Middle Aged; Oxygen Inhalation Therapy; Paraquat; Protein Serine-Threonine Kinases; Pulmonary Fibrosis; Reactive Oxygen Species; Respiratory Insufficiency; Sirolimus; Suicide; TOR Serine-Threonine Kinases; Treatment Failure

Transforming growth factor (TGF)-alpha is a ligand for the epidermal growth factor receptor (EGFR). EGFR activation is associated with fibroproliferative processes in human lung disease and animal models of pulmonary fibrosis. Overexpression of TGF-alpha in transgenic mice causes progressive and severe pulmonary fibrosis; however, the intracellular signaling pathways downstream of EGFR mediating this response are unknown. Using a doxycycline-regulatable transgenic mouse model of lung-specific TGF-alpha expression, we observed increased PCNA protein and phosphorylation of Akt and p70S6K in whole lung homogenates in association with induction of TGF-alpha. Induction in the lung of TGF-alpha caused progressive pulmonary fibrosis over a 7-week period. Daily administration of rapamycin prevented accumulation of total lung collagen, weight loss, and changes in pulmonary mechanics. Treatment of mice with rapamycin 4 weeks after the induction of TGF-alpha prevented additional weight loss, increases in total collagen, and changes in pulmonary mechanics. Rapamycin prevented further increases in established pulmonary fibrosis induced by EGFR activation. This study demonstrates that mammalian target of rapamycin (mTOR) is a major effector of EGFR-induced pulmonary fibrosis, providing support for further studies to determine the role of mTOR in the pathogenesis and treatment of pulmonary fibrosis.

Topics: Animals; Carrier Proteins; Collagen; Disease Models, Animal; Disease Progression; Doxycycline; Enzyme Inhibitors; ErbB Receptors; Erlotinib Hydrochloride; Gene Expression Regulation; Humans; Lung; Mice; Mice, Transgenic; Phosphatidylinositol 3-Kinases; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Proliferating Cell Nuclear Antigen; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pulmonary Fibrosis; Quinazolines; Respiratory Mechanics; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; Transforming Growth Factor alpha; Uteroglobin

Topics: Adult; Cyclophosphamide; Drug Overdose; Drug Therapy, Combination; Herbicides; Humans; Immunosuppressive Agents; Male; Paraquat; Pulmonary Fibrosis; Severity of Illness Index; Sirolimus; Steroids; Suicide, Attempted; Treatment Outcome

Posttransplant lymphoproliferative disorder is a rare and often difficult diagnosis in patients with only cutaneous symptoms. A stepwise approach to diagnosis and classification can lead to successful treatment. We report a case of an EBV-associated posttransplant lymphoproliferative disorder (PTLD) occurring on the face with a primary cutaneous presentation. The appropriate diagnosis was made only after multiple biopsies and special stains. There was near complete resolution with decreased levels of iatrogenic immunosuppression. The diagnosis of Posttransplant lymphoproliferative disorder can be difficult to establish. A proper workup will aid in making an accelerated diagnosis and choosing appropriate treatment options.

Topics: Dose-Response Relationship, Drug; Epstein-Barr Virus Infections; Face; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Lung Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Mycophenolic Acid; Prednisone; Pulmonary Fibrosis; Sirolimus; Skin Diseases

Idiopathic pulmonary fibrosis (IPF) is a progressive chronic disorder of the lower respiratory tract. The main clinical feature is a progressive shortness of breath, particularly on exercise. An overproduction and deposition of collagen and a proliferation of mesenchymal cells are the histopathologic characteristics. Rapamycin is an immunosuppressive agent with antiproliferative effects on mesenchymal cells including fibroblasts. It was this rationale that prompted the authors to administer rapamycin in a case of rapidly progressive IPF.. In a 73-year-old female with a 2-month history of IPF, treatment with steroids and interferon gamma-1b did not improve the detrimental clinical course. Treatment with rapamycin was started; subsequently, clinical condition and objective findings improved markedly within weeks. She is now under treatment for 18 months.. The authors presume that partial remission is related to rapamycin which may be effective in blocking the progressive fibrosis and increased collagen synthesis thought to be pathophysiologically relevant in this disease. Further studies have to show whether rapamycin may be a treatment option in idiopathic pulmonary fibrosis.

Topics: Aged; Dyspnea; Exercise Test; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Long-Term Care; Pulmonary Fibrosis; Retreatment; Sirolimus; Tomography, X-Ray Computed; Treatment Failure

Pulmonary fibrosis is characterized by excessive deposition of extracellular matrix proteins within the pulmonary interstitium. The new macrolide immunosuppressant SDZ RAD, a rapamycin analogue, inhibits growth-factor dependent proliferation of mesenchymal cells and might therefore be of therapeutic interest for the treatment of fibrotic lung disease. In this study the effect of SDZ RAD on lung-collagen accumulation in the bleomycin model of pulmonary fibrosis in rats was investigated. SDZ RAD (2.5 mg x kg(-1) x day(-1)) or drug vehicle were administered orally by daily gavage. Successful dosing was confirmed by measuring splenic weight. Total lung-collagen content was measured by high-performance liquid chromatographic quantitation of hydroxyproline. In animals given bleomycin and drug vehicle, total lung collagen was increased by 182+/-11% (mean+/-SEM) compared with saline controls at 14 days (p<0.001). The increase in lung-collagen accumulation was reduced by 75+/-12% (p<0.01) in animals given SDZ RAD and was accompanied by a concomitant 56+/-6% (p<0.001) reduction in lung weight. SDZ RAD is currently in clinical trials for the prevention of solid organ graft rejection, another condition characterized by excessive extracellular matrix production. The authors propose that SDZ RAD warrants evaluation as a novel therapeutic agent for fibrotic lung disease.

Topics: Animals; Antimetabolites, Antineoplastic; Bleomycin; Collagen; Everolimus; Hydroxyproline; Immunosuppressive Agents; Lung; Male; Organ Size; Pulmonary Fibrosis; Rats; Rats, Inbred Lew; Sirolimus; Spleen