Effects of amiodarone on lung tissue mechanics and parenchyma remodeling

We studied the results of chronic oral administration of amiodarone on in vitro lung tissue mechanics, light and electron microscopy. Fifteen Wistar male rats were divided into three groups. In control (CTRL) group animals received saline (0.5 mL/day). In amiodarone (AMIO) groups, amiodarone was administered by gavage at a dose of 175 mg/kg 5 days per week for 6 (6AMIO) or 12 weeks (12AMIO). Lung tissue strips were analyzed 24 h after the last drug administration. Tissue resistance and elastance were higher in 6AMIO and 12AMIO than in CTRL, while hysteresivity was similar in all groups. Total amount of collagen fibers in lung parenchyma increased progressively with the time course of the lesion. However, at 6 weeks there was an increase in the amount of type III collagen fibers, while in 12AMIO mainly type I collagen fibers were found. In our study amiodarone increased lung tissue impedance that was accompanied by matrix remodeling and lesion of type II pneumocytes. (C) 2008 Elsevier B.V. All rights reserved.PRONEX-MCTPRONEX-FAPERJCNPqFAPERJCAPE

Repeated Administration of Bone Marrow-Derived Cells Prevents Disease Progression in Experimental Silicosis

Background/Aims: Bone marrow-derived cells (BMDCs) reduced mechanical and histologic changes in the lung in a murine model of silicosis, but these beneficial effects did not persist in the course of lung injury. We hypothesized that repeated administration of BMDCs may decrease lung inflammation and remodeling thus preventing disease progression. Methods: One hundred and two C57BL/6 mice were randomly divided into SIL (silica, 20 mg intratracheally [IT]) and control (C) groups (saline, IT). C and SIL groups were further randomized to receive BMDCs (2×106 cells) or saline IT 15 and 30 days after the start of the protocol. Results: By day 60, BMDCs had decreased the fractional area of granuloma and the number of polymorphonuclear cells, macrophages (total and M1 phenotype), apoptotic cells, the level of transforming growth factor (TGF)-β‚ and types I and III collagen fiber content in the granuloma. In the alveolar septa, BMDCs reduced the amount of collagen and elastic fibers, TGF-β, and the number of M1 and apoptotic cells. Furthermore, interleukin (IL)-1β, IL-1R1, caspase-3 mRNA levels decreased and the level of IL-1RN mRNA increased. Lung mechanics improved after BMDC therapy. The presence of male donor cells in lung tissue was not observed using detection of Y chromosome DNA. Conclusion: repeated administration of BMDCs reduced inflammation, fibrogenesis, and elastogenesis, thus improving lung mechanics through the release of paracrine factors

Intratracheal Instillation of Lipopolymeric Vectors and the Effect on Mice Lung Physiology

Background/Aims: The current study compared the effects of intratracheal administration of different lipopolymeric vectors on lung function and histology in normal mice. Methods: Forty-eight BALB/c mice were randomly divided into 8 groups (6/group). All animals received intratracheal instillation of the following suspensions: polymerized [(A) 1,2-dimyristoyl-sn-glycero-3- phosphocholine (DMPC):1,2-bis-(tricosa-10,12-diynoyl)-sn-glycero-3- phosphocholine (DC8,9PC):1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), (B) DMPC:DC8,9PC:stearylamine (SA), (C) DMPC:DC8,9PC:myristoylcholine chloride (MCl)]; nonpolymerized [(D) DMPC:DC8,9PC:DOTAP, (E) DMPC:DC8,9PC:SA, (F) DMPC:DC8,9PC:MCl] together with plasmid DNA; vehicle (control), and pDsRed2-N1 plasmid DNA (DNA). At 24 h, the survival rate, lung mechanics (resistive and viscoelastic pressure, static elastance) and morphometry were analyzed. Results: The survival rate was 50% in D, 40% in E and F, and 100% in the CTRL, DNA, A, B and C groups. Animals from groups D, E, and F that died presented diffuse pulmonary hemorrhagic capillaritis. Lung mechanics, the fraction of normal and collapsed alveoli, as well as the number of polymorphonuclear and mononuclear cells in lung tissue were similar in all surviving mice. Conclusion: Intratracheal instillation of polymerized particles is safe compared with nonpolymerized formulations and may be used for future gene/drug therapy.Fil: Xisto, Debora G.. Universidade Federal do Rio de Janeiro; BrasilFil: Temprana, Carlos Facundo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Biomembranas; ArgentinaFil: Martini, Sabrina V.. Universidade Federal do Rio de Janeiro; BrasilFil: Silva, Adriana L.. Universidade Federal do Rio de Janeiro; BrasilFil: Abreu, Soraia G.. Universidade Federal do Rio de Janeiro; BrasilFil: Silva, Johnatas D.. Universidade Federal do Rio de Janeiro; BrasilFil: Crosseti, Julia. Universidade Federal do Rio de Janeiro; BrasilFil: Rocco, Patricia R. M.. Universidade Federal do Rio de Janeiro; BrasilFil: Alonso, Silvia del Valle. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Biomembranas; ArgentinaFil: Morales, Marcelo M.. Universidade Federal do Rio de Janeiro; Brasi

Insult-dependent effect of bone marrow cell therapy on inflammatory response in a murine model of extrapulmonary acute respiratory distress syndrome

Abstract Introduction Administration of bone marrow-derived cells produces beneficial effects in experimental extrapulmonary acute respiratory distress syndrome (ARDS). However, there are controversies regarding the effects of timing of cell administration and initial insult severity on inflammatory response. We evaluated the effects of bone marrow-derived mononuclear cells (BMDMC) in two models of extrapulmonary ARDS once lung morphofunctional changes had already been installed. Methods BALB/c mice received lipopolysaccharide (LPS) intraperitoneally (5 mg/kg in 0.5 ml saline) or underwent cecal ligation and puncture (CLP). Control mice received saline intraperitoneally (0.5 ml) or underwent sham surgery. At 24 hours, groups were further randomized to receive saline or BMDMC (2 × 106) intravenously. Lung mechanics, histology, and humoral and cellular parameters of lung inflammation and remodeling were analyzed 1, 3 and 7 days after ARDS induction. Results BMDMC therapy led to improved survival in the CLP group, reduced lung elastance, alveolar collapse, tissue and bronchoalveolar lavage fluid cellularity, collagen fiber content, and interleukin-1β and increased chemokine (keratinocyte-derived chemokine and monocyte chemotactic protein-1) expression in lung tissue regardless of the experimental ARDS model. Intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression in lung tissue increased after cell therapy depending on the insult (LPS or CLP). Conclusions BMDMC therapy at day 1 successfully reduced lung inflammation and remodeling, thus contributing to improvement of lung mechanics in both extrapulmonary ARDS models. Nevertheless, the different inflammatory responses induced by LPS and CLP resulted in distinct effects of BMDMC therapy. These data may be useful in the clinical setting, as they suggest that the type of initial insult plays a key role in the outcome of treatment

Protective effects of bone marrow mononuclear cell therapy on lung and heart in an elastase-induced emphysema model

We hypothesized that bone marrow-derived mononuclear cell (BMDMC) therapy protects the lung and consequently the heart in experimental elastase-induced emphysema. Twenty-four female C57BL/6 mice were intratracheally instilled with saline (C group) or porcine pancreatic elastase (E group) once a week during 4 weeks. C and E groups were randomized into subgroups receiving saline (SAL) or male BMDMCs (2 x 10(6), CELL) intravenously 3 h after the first saline or elastase instillation. Compared to E-SAL group, E-CELL mice showed, at 5 weeks: lower mean linear intercept, neutrophil infiltration, elastolysis, collagen fiber deposition in alveolar septa and pulmonary vessel wall, lung cell apoptosis, right ventricle wall thickness and area, higher endothelial growth factor and insulin-like growth factor mRNA expressions in lung tissue, and reduced platelet-derived growth factor, transforming growth factor-beta, and caspase-3 expressions. In conclusion, BMDMC therapy was effective at modulating the inflammatory and remodeling processes in the present model of elastase-induced emphysema. (c) 2012 Elsevier B.V. All rights reserved.Centres of Excellence Program (PRONEX-FAPERJ)Centres of Excellence Program (PRONEXFAPERJ)Brazilian Council for Scientific and Technological Development (MCT/CNPq)Brazilian Council for Scientific and Technological Development (MCT/CNPq)Carlos Chagas Filho Rio de Janeiro State Research Supporting Foundation (FAPERJ)Carlos Chagas Filho Rio de Janeiro State Research Supporting Foundation (FAPERJ)Sao Paulo State Research Support Foundation (FAPESP)Sao Paulo State Research Support Foundation (FAPESP)National Institute of Science and Technology of Drugs and Medicine (INCTINOFAR)National Institute of Science and Technology of Drugs and Medicine (INCT-INOFAR)Coordination for the Improvement of Higher Level Personnel (CAPES)Coordination for the Improvement of Higher Level Personnel (CAPES

Effects of chronic L-NAME treatment lung tissue mechanics, eosinophilic and extracellular matrix responses induced by chronic pulmonary inflammation

The importance of lung tissue in asthma pathophysiology has been recently recognized. Although nitric oxide mediates smooth muscle tonus control in airways, its effects on lung tissue responsiveness have not been investigated previously. We hypothesized that chronic nitric oxide synthase (NOS) inhibition by N-omega-nitro-L-arginine methyl ester (L-NAME) may modulate lung tissue mechanics and eosinophil and extracellular matrix remodeling in guinea pigs with chronic pulmonary inflammation. Animals were submitted to seven saline or ovalbumin exposures with increasing doses (1 similar to 5 mg/ml for 4 wk) and treated or not with L-NAME in drinking water. After the seventh inhalation (72 h), animals were anesthetized and exsanguinated, and oscillatory mechanics of lung tissue strips were performed in baseline condition and after ovalbumin challenge (0.1%). Using morphometry, we assessed the density of eosinophils, neuronal NOS (nNOS)- and inducible NOS (iNOS)-positive distal lung cells, smooth muscle cells, as well as collagen and elastic fibers in lung tissue. Ovalbumin-exposed animals had an increase in baseline and maximal tissue resistance and elastance, eosinophil density, nNOS- and iNOS-positive cells, the amount of collagen and elastic fibers, and isoprostane-8-PGF(2 alpha) expression in the alveolar septa compared with controls (P < 0.05). L-NAME treatment in ovalbumin-exposed animals attenuated lung tissue mechanical responses (P < 0.01), nNOS- and iNOS-positive cells, elastic fiber content (P < 0.001), and isoprostane-8-PGF(2 alpha) in the alveolar septa (P < 0.001). However, this treatment did not affect the total number of eosinophils and collagen deposition. These data suggest that NO contributes to distal lung parenchyma constriction and to elastic fiber deposition in this model. One possibility may be related to the effects of NO activating the oxidative stress pathway

Intratracheal instillation of bone marrow-derived cell in an experimental model of silicosis

The time course of lung mechanics, histology, and inflammatory and fibrogenic mediators are analysed after intratracheal instillation (IT) of bone marrow-derived cells (BMDC) in a model of silicosis. C57BL/6 mice were randomly divided into SIL (silica, 20 mg IT) and control (CTRL) groups (saline IT). At day 15, mice received saline or BMDC (2 × 10 6 cells) IT. The biodistribution of technetium-99m BMDC was higher in lungs compared with other organs. At days 30 and 60, lung mechanics, the area of granulomatous nodules, and mRNA expression of IL-1β and TGF-β were higher in SIL than CTRL animals. BMDC minimized changes in lung mechanics, the area of granulomatous nodules, and total cell infiltration at day 30, but these effects were no longer observed at day 60. Conversely, BMDC avoided the expression of IL-1β at days 30 and 60 and TGF-β only at day 30. In conclusion, BMDC therapy improved lung mechanics and histology, but this beneficial effect was not maintained in the course of injury