tretinoin and Pulmonary-Fibrosis

Classically, emphysema has been believed to develop when mediators of tissue injury exceed protective mechanisms within the lung. Evidence also supports the concept that tissue destruction represents a balance between tissue injury and tissue repair. In this context, cigarette smoke is directly toxic to cells within the lung and can impair the repair functions of fibroblasts, epithelial cells, and mesenchymal cells. This may occur in the absence of overt cytotoxicity and may result from alteration of selected biochemical pathways. A variety of repair functions can be affected, including chemotaxis, proliferation, production of extracellular matrix, and remodeling of extracellular matrix. Finally, cigarette smoke can damage DNA but can also compromise apoptosis. As a result, DNA repair mechanisms can be initiated, leading to recovery of cells that potentially contain somatic cell mutations. This pathway may contribute not only to the development of cancer but to the persistent abnormalities in tissue structure that characterize chronic obstructive pulmonary disease. Understanding the mechanisms that mediate normal tissue repair and understanding the bases for altered tissue repair in the face of cigarette smoking offer new opportunities designed to address the structural alterations that characterize chronic obstructive pulmonary disease.

Topics: Animals; Apoptosis; DNA Damage; DNA Repair; Emphysema; Humans; Pulmonary Alveoli; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Smoking; Tretinoin; Wound Healing

Retinoic acid is the bioactive metabolite of vitamin A and considerable evidence implicates retinoic acid as important signaling molecule during normal lung development and retinoid signaling elements, such as receptors and binding proteins have been described in the developing lung. Alveolization, or the formation of alveoli during lung development, is essentially completed in the neonatal period, and little neo-alveolization occurs in the adult lung. Recently, several studies have shown that retinoic acid is effective in promoting alveolization in neonatal rats, in adult rats with elastase-induced emphysema. However, the exact mechanism governing this regeneration is still unknown. Recent advanced technologies will clarify the role of retinoic acid in alveolization and even how alveolization occurs, leading to regeneration therapy for the devastating lung diseases, such as emphysema and fibrotic disorders.

Topics: Animals; Humans; Lung Diseases; Pulmonary Alveoli; Pulmonary Emphysema; Pulmonary Fibrosis; Regeneration; Signal Transduction; Tretinoin

The role of all-trans retinoic acid (ATRA) in pulmonary fibrosis is relatively unknown, although this metabolite modulates cell differentiation, proliferation, and development. We aimed to evaluate the role of ATRA in bleomycin-induced pulmonary fibrosis, and whether the mechanism involves EphA2-EphrinA1 and PI3K-Akt signaling. We evaluated three groups of mice: a control group (intraperitoneal DMSO injection 3 times weekly after PBS instillation), bleomycin group (intraperitoneal DMSO injection 3 times weekly after bleomycin instillation), and bleomycin + ATRA group (intraperitoneal ATRA injection 3 times weekly after bleomycin instillation). The cell counts and protein concentration in the bronchoalveolar lavage fluid (BALF), changes in histopathology, Ashcroft score, hydroxyproline assay, expression of several signal pathway proteins including EphA2-EphrinA1, and PI3K-Akt, and cytokine levels were compared among the groups. We found that bleomycin significantly increased the protein concentration in the BALF, Ashcroft score in lung tissue, and hydroxyproline contents in lung lysates. Furthermore, bleomycin upregulated EphA2, EphrinA1, PI3K 110γ, Akt, IL-6 and TNF-α. However, administration of ATRA attenuated the upregulation of EphA2-EphrinA1 and PI3K-Akt after bleomycin instillation, and decreased pulmonary fibrosis. In addition, ATRA suppressed IL-6 and TNF-α production induced by bleomycin-induced injury. Collectively, these data suggest that ATRA attenuates bleomycin-induced pulmonary fibrosis by regulating EphA2-EphrinA1 and PI3K-Akt signaling.

Topics: Animals; Cytokines; Down-Regulation; Ephrin-A1; Lung; Male; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis; Receptor, EphA2; Signal Transduction; Tretinoin

The transforming growth factor-β1 (TGF-β1)/Smad3 signaling pathway has a central role in pathogenesis of lung fibrosis. In the present study, we investigated if all-trans retinoic acid (ATRA) could attenuate fibrosis in bleomycin (BLM)-induced lung fibrosis in rats through regulating TGF-β1/Smad3 signaling. Beginning on day 14 after BLM administration, the ATRA I and II groups of rats received daily oral administration of ATRA for 14 days. All rats were killed on day 28. Lung tissue sections were prepared and subject to histological assessment, and expression levels of proteins involved in the TGF-β1 signaling cascade and epithelial-mesenchymal transition (EMT) were evaluated by transmission electron microscopy (TEM), quantitative real-time polymerase chain reaction (qRT-PCR), western blot procedure, and immunohistochemical or immunofluorescence staining. BLM significantly increased the alveolar septum infiltrates, inflammatory cell infiltrates, and collagen fibers. These BLM-induced changes were significantly ameliorated by ATRA treatment. In addition, BLM significantly increased levels of lung fibrosis markers α-SMA, hydroxyproline (Hyp), collagen I, Snail, and Twist, whereas significantly decreased E-cadherin expression. ATRA treatment largely reversed BLM-induced changes in these lung fibrosis markers. ATRA also blocked BLM-induced activation of the TGF-β1/Smad3 signaling pathway in lung tissues, including expression of TGF-β1, Smad3, p-Smad3, zinc-finger E-box-binding homeobox 1 and 2 (ZEB1 and ZEB2), and the high-mobility group AT-hook 2 (HMGA2). Our results suggest that ATRA may have potential therapeutic value for lung fibrosis treatment.

Topics: Animals; Biomarkers; Bleomycin; Collagen; Disease Models, Animal; Down-Regulation; Epithelial-Mesenchymal Transition; HMGA2 Protein; Homeodomain Proteins; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Smad3 Protein; Transcription Factors; Transforming Growth Factor beta1; Tretinoin; Zinc Finger E-box-Binding Homeobox 1

Much evidence suggests that immune imbalance in the lung plays a crucial role in the development of pulmonary fibrosis. Recently, all-trans retinoic acid (ATRA) shifting the regulatory T/T-helper 17 (Treg/Th17) profile had been proven in some diseases. However, to date, the effect of ARTA of pulmonary fibrosis has not been examined from this aspect. The objective of this study was to study the effect of ATRA on bleomycin-induced pulmonary fibrosis in mice and its possible mechanism. Pulmonary fibrosis was induced in C57BL/6 male mice by intratracheal instillation of bleomycin (5 mg.kg(-1)), which were randomly divided into control, bleomycin, and ATRA groups. Five mice in each group were sacrificed on day 28 after intratracheal instillation. Hemotoxylin and eosin (H&E) and Masson staining were used for pathological examination, and hydroxyproline in lung tissue was measured. Interleukin (IL)-17A protein expression was observed in lung with immunohistochemistry. The expression of IL-17A, IL-10, IL-6, and transforming growth factor (TGF)-β mRNAs were detected by reverse transcriptase-polymerase chain reaction (RT-PCR). Th17 and Treg expression in spleen lymphocytes were measured by flow cytometry. H&E and masson staining and expression of hydroxyproline showed that ATRA significantly alleviated lung fibrosis than in the bleomycin group. The expression of IL-17A, IL-10, IL-6, and TGF-β mRNAs were higher in the bleomycin group than in the normal group. ATRA can decrease these cytokines except for IL-10. CD4+CD25+ Treg cell ratio in the bleomycin group was significantly lower than normal, but CD4+IL-17+ T cells was higher; ARTA reversed this kind of expression. ATRA may ease the bleomycin-induced pulmonary fibrosis by inhibiting the expression of IL-6 and TGF-β, shifting the Treg/Th17 ratio and reducing the secretion of IL-17A.

Topics: Animals; Antibiotics, Antineoplastic; Bleomycin; CD4-Positive T-Lymphocytes; Cell Count; Disease Models, Animal; Drug Therapy, Combination; Gene Expression; Hydroxyproline; Interleukins; Lung; Male; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta; Tretinoin

Monocrotaline (MCT), a pyrrolizidine alkaloid extracted from the shrub Crotalaria spectabilis, induces in the lungs of many mammalian species severe hypertension and fibrosis. Previous work with MCT-induced lung disease in rats has shown that some of the steps to progressive fibrosis can be interrupted or decreased by intervention with retinoic acid (RA) or with the angiotensin converting enzyme inhibitor, captopril. This report emphasizes the pathology and cytokines present in lungs of rats in the MCT model of hypertension and fibrosis in 8 treatment groups, six per group: (1) controls, not treated; (2) captopril; (3) RA; (4) combined captopril and RA. Groups 5-8 replicated groups 1-4 and also received MCT subcutaneously. Tissues were harvested at 28 days for histopathology and measurement of cytokines TGFbeta, TNFalpha, interleukin 6, and IFN_. TGFbeta was depressed at 28 days by MCT, an effect reversed by a combination of captopril and RA. RA influences production of an important Th1 cytokine, IFN_, and demonstrated the greatest limitation of MCT-induced TNFalpha. The MCT-induced lung pathology of vasculitis, interstitial pneumonia and fibrosis was limited by captopril. Smooth muscle actin was overexpressed in MCT treated animals receiving RA, an effect reduced with captopril. Overall, the study confirmed the existence of a protective effect for both captopril and RA from MCT-induced lung damage at 30 days. No synergistic or antagonistic activity was observed when the two drugs were administered together. Each of the drugs exerts different and particular effects on serum and tissue levels of various cytokines, suggesting that each drug is efficient at different points of attack in the control of lung fibrosis.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Captopril; Cytokines; Disease Models, Animal; Male; Monocrotaline; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; Tretinoin

Although radiotherapy is effective in treating lung cancers, resultant pulmonary injury is the main obstacle. Pulmonary fibrosis is characterized by progressive worsening in pulmonary function leading to high incidence of death. Currently, however, there has been little progress in effective preventive and therapeutic strategies.. Previously, we reported that all-trans-retinoic acid (ATRA) reduced both irradiation-induced interleukin (IL)-6 production in lung fibroblasts and IL-6-dependent cell growth, and also directly inhibited the proliferation of lung fibroblasts after irradiation. In this study, we examined the preventive effect of ATRA on the progression of lung fibrosis both in irradiated and bleomycin-treated mice.. We performed histologic examinations and quantitative measurements of IL-6, transforming growth factor (TGF)-beta(1), and collagen type Ialpha1 (COL1A1) in irradiated and bleomycin- treated mouse lung tissues with or without the administration of ATRA.. Lethal irradiation effect was reduced by intraperitoneal administration of ATRA, and the overall survival rate at 16 wk was 30.0% without ATRA (n = 11), whereas it was 81.8% (n = 10) in the treatment group (p = 0.04). In vitro studies disclosed that the administration of ATRA reduced (1) irradiation-induced production of IL-6, TGF-beta(1), and collagen from IMR90 cells, and (2) IL-6-dependent proliferation and TGF-beta(1)-dependent transdifferentiation of the cells, which could be the mechanism underlying the preventive effect of ATRA on lung fibrosis. Furthermore, ATRA ameliorated bleomycin-induced fibrosis in mouse lung tissues.. These data may provide a rationale to explore clinical use of ATRA for the prevention of radiation-induced lung fibrosis and other pathologic conditions involving pulmonary fibrosis.

Topics: Animals; Bleomycin; Cells, Cultured; Collagen; Collagen Type I; Collagen Type I, alpha 1 Chain; Female; Fluorescent Antibody Technique; Humans; Interleukin-6; Lung; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis; Transforming Growth Factor beta1; Tretinoin

All-trans-retinoic acid (ATRA) has anti-fibrotic and antiinflammatory properties, and may be useful as a therapeutic agent in lung fibrosis. To test this hypothesis we investigated the effect of ATRA on bleomycin-induced lung fibrosis in Sprague-Dawley rats. Treatment groups included: (1) a single intratracheal (i.t.) instillation of bleomycin and daily intraperitoneal (i.p.) injection of 0.5 mg/kg per day ATRA; (2) i.t. bleomycin and i.p. ATRA, 2 mg/kg per day, (3) i.t. bleomycin and i.p. diluent (cottonseed oil); (4) i.t. saline and i.p. ATRA, 0.5 mg/kg per day, (5) i.t. saline and i.p. ATRA, 2 mg/kg per day; and (6) i.t. saline and i.p. diluent. Animals were studied 14 days after i.t. instillation. Lung injury was evaluated by total and differential cell count in bronchoalveolar lavage fluid, by a semi-quantitative morphological index of lung injury, and by biochemical analysis of lung hydroxyproline content. Overt signs of lung injury were apparent in bleomycin-treated rats by all measures. These changes were not affected by treatment with ATRA at either dose. This study does not support the use of ATRA to prevent or ameliorate lung fibrosis.

Topics: Animals; Antineoplastic Agents; Bleomycin; Disease Models, Animal; Injections, Intraperitoneal; Lung; Pulmonary Fibrosis; Random Allocation; Rats; Rats, Sprague-Dawley; Tretinoin

We report here the spontaneous in vitro transformation of blood monocytes into fibroblasts in a patient who developed pulmonary fibrosis following ciclosporin-mediated immunosuppression, necessitated by heart transplantation. The blood monocytes with this capacity expressed HLA-DR specificity. Monocytes/macrophages were identified by immunofluorescence using monoclonal antibodies against a specific monocyte/macrophage antigen, while the neo-fibroblasts were identified by electron microscopy and immunofluorescence using monoclonal antibodies against a cytoplasmic enzyme specifically involved in the synthesis of collagen. The secretion of collagen was demonstrated using antibodies against collagen. Both the monocytes/macrophages and the neo-fibroblasts express macrophage and fibroblast markers and are able to synthesize collagen. The all-trans retinoic acid derivative (all-trans RA) inhibits this in vitro transformation of HLA-DR monocytes/macrophages into neo-fibroblasts. Therefore, the possible therapeutic role of all-trans RA in controlling the development of fibrosis remains open to investigation. Until now, no efficient therapy is known for fibrotic diseases which are often lethal when affecting the lungs.

Topics: Aged; Cell Transformation, Neoplastic; Cells, Cultured; Cyclosporine; Fibroblasts; HLA-DR Antigens; Humans; Immunocompromised Host; In Vitro Techniques; Male; Monocytes; Pulmonary Fibrosis; Tretinoin