Nayra Cárdenes

University of Pittsburgh

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ATF3 Pleiotropic Functions Over IPF Lung Fibroblast

Tamara Cruz Diana Álvarez John Sembrat Jordan Bullock Nayra Cárdenes

10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a5412

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Modified mesenchymal stem cells using miRNA transduction alter lung injury in a bleomycin model

AJP Lung Cellular and Molecular Physiology (2017)

Luai Huleihel Jacobo Sellarés Nayra Cárdenes Diana Álvarez Rosa Faner

Although different preclinical models have demonstrated a favorable role for bone marrow-derived mesenchymal stem cells (B-MSC) in preventing fibrosis, this protective effect is not observed with late administration of these cells, when fibrotic changes are consolidated. We sought to investigate whether the late administration of B-MSCs overexpressing microRNAs (miRNAs) let-7d (antifibrotic) or miR-154 (profibrotic) could alter lung fibrosis in a murine bleomycin model. Using lentiviral vectors, we transduced miRNAs (let-7d or miR-154) or a control sequence into human B-MSCs. Overexpression of let-7d or miR-154 was associated with changes in the mesenchymal properties of B-MSCs and in their cytokine expression. Modified B-MSCs were intravenously administered to mice at day 7 after bleomycin instillation, and the mice were euthanized at day 14 Bleomycin-injured animals that were treated with let-7d cells were found to recover quicker from the initial weight loss compared with the other treatment groups. Interestingly, animals treated with miR-154 cells had the lowest survival rate. Although a slight reduction in collagen mRNA levels was observed in lung tissue from let-7d mice, no significant differences were observed in Ashcroft score and OH-proline. However, the distinctive expression in cytokines and CD45-positive cells in the lung suggests that the differential effects observed in both miRNA mice groups were related to an effect on the immunomodulation function. Our results establish the use of miRNA-modified mesenchymal stem cells as a potential future research in lung fibrosis.

10.1152/ajplung.00323.2016

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Citations (40)

Mesenchymal Stem Cells: A Promising Therapy for the Acute Respiratory Distress Syndrome

Respiration (2013)

Nayra Cárdenes Eder Cáceres Militza Romagnoli Mauricio Rojas

Acute respiratory distress syndrome (ARDS) is a pulmonary syndrome with growing prevalence and high mortality and morbidity that increase with age. There is no current therapy able to restore pulmonary function in ARDS patients. Preclinical models of ARDS have demonstrated that intratracheal or systemic administration of mesenchymal stem cells (MSCs) protects the lung against injury. The mechanisms responsible for the protective effects are multiple, including the secretion of multiple paracrine factors capable of modulating the immune response and restoring epithelial and endothelial integrity. Recent studies have demonstrated that MSCs can also control oxidative stress, transfer functional mitochondria to the damaged cells, and control bacterial infection by secretion of antibacterial peptides. These characteristics make MSCs promising candidates for ARDS therapy.

Stem Cell Therapy

Cell therapy

10.1159/000347072

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Citations (56)

Ex vivo lung perfusion as a human platform for preclinical small molecule testing

JCI Insight (2018)

Nathaniel M. Weathington Diana Álvarez John Sembrat Josiah E. Radder Nayra Cárdenes

The acute respiratory distress syndrome (ARDS) causes an estimated 70,000 US deaths annually. Multiple pharmacologic interventions for ARDS have been tested and failed. An unmet need is a suitable laboratory human model to predictively assess emerging therapeutics on organ function in ARDS. We previously demonstrated that the small molecule BC1215 blocks actions of a proinflammatory E3 ligase–associated protein, FBXO3, to suppress NF-κB signaling in animal models of lung injury. Ex vivo lung perfusion (EVLP) is a clinical technique that maintains lung function for possible transplant after organ donation. We used human lungs unacceptable for transplant to model endotoxemic injury with EVLP for 6 hours. LPS infusion induced inflammatory injury with impaired oxygenation of pulmonary venous circulation. BC1215 treatment after LPS rescued oxygenation and decreased inflammatory cytokines in bronchoalveolar lavage. RNA sequencing transcriptomics from biopsies taken during EVLP revealed robust inflammatory gene induction by LPS with a strong signal for NF-κB–associated transcripts. BC1215 treatment reduced the LPS induction of genes associated with inflammatory and host defense gene responses by Gene Ontology (GOterm) and pathways analysis. BC1215 also significantly antagonized LPS-mediated NF-κB activity. EVLP may provide a unique human platform for preclinical study of chemical entities such as FBXO3 inhibitors on tissue physiology.

Ex vivo

Proinflammatory cytokine

10.1172/jci.insight.95515

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Citations (27)

Parabiotic model for differentiating local and systemic effects of continuous and intermittent hypoxia

Journal of Applied Physiology (2014)

Marta Torres Mauricio Rojas Noelia Campillo Nayra Cárdenes Josep M. Montserrat

Hypoxia can be damaging either because cells are directly sensitive to low oxygen pressure in their local microenvironment and/or because they are exposed to circulating factors systemically secreted in response to hypoxia. The conventional hypoxia model, breathing hypoxic air, does not allow one to distinguish between these local and systemic effects. Here we propose and validate a model for differentially applying local and systemic hypoxic challenges in an animal. We used parabiosis, two mice sharing circulation by surgical union through the skin, and tested the hypothesis that when one of the parabionts breathes room air and the other one is subjected to hypoxic air, both mice share systemic circulation but remain normoxic and hypoxic, respectively. We tested two common hypoxic paradigms in 10 parabiotic pairs: continuous hypoxia (10% O2) mimicking chronic lung diseases, and intermittent hypoxia (40 s, 21% O2; 20 s, 5% O2) simulating sleep apnea. Arterial oxygen saturation and oxygen partial pressure at muscle tissue were measured in both parabionts. Effective cross-circulation was assessed by intraperitoneally injecting a dye in one of the parabionts and measuring blood dye concentration in both animals after 2 h. The results confirmed the hypothesis that tissues of the parabiont under room air were perfused with normally oxygenated blood and, at the same time, were exposed to all of the systemic mediators secreted by the other parabiont actually subjected to hypoxia. In conclusion, combination of parabiosis and hypoxic/normoxic air breathing is a novel approach to investigate the effects of local and systemic hypoxia in respiratory diseases.

Hypoxia

Parabiosis

Systemic circulation

Intermittent hypoxia

10.1152/japplphysiol.00858.2014

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Citations (6)

The Use of GMP-Produced Bone Marrow-Derived Stem Cells in Combination with Extracorporeal Membrane Oxygenation in ARDS: An Animal Model

ASAIO Journal (2017)

Ergin Koçyıldırım Nayra Cárdenes Anthony E. Ting Eder Cáceres C. Bermúdez

Acute respiratory distress syndrome (ARDS) is the result of a wide variety of disorders, which can be associated with different clinical disorders or systemic diseases directly affecting the lungs. Currently, the only existing therapy is limited to supportive care. In a 6 hour pilot study, we analyzed the use of the combination of both stem cell and extracorporeal membrane oxygenation (ECMO) strategies to prevent or treat severe lung injury. A total of 11 sheep were used. Five sheep received Escherichia coli endotoxin as a control group (group 1). Three sheep that received E. coli endotoxin were treated with veno-venous ECMO support in group 2. In group 3, 3 sheep received a dose of clinical grade good manufacturing practice (GMP)-produced MultiPotent Adult Progenitor cells (MAPC) intratracheally after the end of the infusion of E. coli endotoxin, followed by ECMO support. The respiratory parameters by means of blood gas results, measurements of lung injury, inflammatory responses, and integrity of the alveolar capillary barrier after the infusion of these cells were analyzed. Our data suggest that the combination of ECMO and stem cell therapy showed better histopathologic changes with less inflammation. We believe that the combination of stem cells with the ECMO treatment may be useful in future studies investigating the diagnosis, treatment, and prevention of ARDS.

10.1097/mat.0000000000000566

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Citations (23)

Impaired NK Activity in the IPF Lungs

Tamara Cruz J. Minxue Tracy Tabib John Sembrat Anna Bondonese

10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a3077

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The potential role of intracellular heat shock protein 70 deficiency in aging and pulmonary fibrosis

Jacobo Sellarés Katelynn J. Thiel Nayra Cárdenes Frank Schneider Joseph M. Pilewski

Idiopathic Pulmonary Fibrosis (IPF) is a disease that may have pathophysiological similarities to some of the mechanisms involved in aging. Loss of proteostasis is one of the current hallmarks of aging and heat shock proteins (Hsp) are currently considered chaperones that regulate proteostasis. Preliminary data have demonstrated that Hsp-70 might be associated with IPF. We sought to investigate the potential association between the deficiency of Hsp70 with aging and IPF. Hsp70 expression was assessed using immunofluorescence in human lungs, and found that Hsp70 was not expressed in older compared to younger IPF tissues. . We also observed decreased Hsp70 mRNA and protein in primary fibroblasts from IPF versus normal donors. Treatment of primary human lung fibroblasts in vitro with TGF-β1 decreased Hsp70 in parallel with increased extracellular matrix proteins, collagen and fibronectin. Young Hsp70 knock-out mice (8-10 weeks) were subjected to an inhalational bleomycin model of pulmonary fibrosis and demonstrated accelerated fibrosis versus wild-type controls. No spontaneous fibrosis was observed in older knock-out mice (> 20 weeks). We therefore conclude that reduced Hsp70 protein is associated with pulmonary fibrosis. Interventions aimed at restoring normal expression of Hsp70 represent a novel therapeutic strategy for pulmonary fibrosis.

Proteostasis

Pirfenidone

Pathophysiology

10.1183/1393003.congress-2017.pa1027

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Infusion of freshly isolated autologous bone marrow derived mononuclear cells prevents endotoxin-induced lung injury in an ex-vivo perfused swine model

Stem Cell Research & Therapy (2013)

Mauricio Rojas Richard Parker Natalie Thorn Claudia Corredor Smita S. Iyer

The acute respiratory distress syndrome (ARDS), affects up to 150,000 patients per year in the United States. We and other groups have demonstrated that bone marrow derived mesenchymal stromal stem cells prevent ARDS induced by systemic and local administration of endotoxin (lipopolysaccharide (LPS)) in mice. A study was undertaken to determine the effects of the diverse populations of bone marrow derived cells on the pathophysiology of ARDS, using a unique ex-vivo swine preparation, in which only the ventilated lung and the liver are perfused with autologous blood. Six experimental groups were designated as: 1) endotoxin alone, 2) endotoxin + total fresh whole bone marrow nuclear cells (BMC), 3) endotoxin + non-hematopoietic bone marrow cells (CD45 neg), 4) endotoxin + hematopoietic bone marrow cells (CD45 positive), 5) endotoxin + buffy coat and 6) endotoxin + in vitro expanded swine CD45 negative adherent allogeneic bone marrow cells (cultured CD45neg). We measured at different levels the biological consequences of the infusion of the different subsets of cells. The measured parameters were: pulmonary vascular resistance (PVR), gas exchange (PO2), lung edema (lung wet/dry weight), gene expression and serum concentrations of the pro-inflammatory cytokines IL-1β, TNF-α and IL-6. Infusion of freshly purified autologous total BMCs, as well as non-hematopoietic CD45(-) bone marrow cells significantly reduced endotoxin-induced pulmonary hypertension and hypoxemia and reduced the lung edema. Also, in the groups that received BMCs and cultured CD45neg we observed a decrease in the levels of IL-1β and TNF-α in plasma. Infusion of hematopoietic CD45(+) bone marrow cells or peripheral blood buffy coat cells did not protect against LPS-induced lung injury. We conclude that infusion of freshly isolated autologous whole bone marrow cells and the subset of non-hematopoietic cells can suppress the acute humoral and physiologic responses induced by endotoxemia by modulating the inflammatory response, mechanisms that do not involve engraftment or trans-differentiation of the cells. These observations may have important implications for the design of future cell therapies for ARDS.

Ex vivo

10.1186/scrt174

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Citations (36)

Intracellular Heat Shock Protein 70 Deficiency in Pulmonary Fibrosis

American Journal of Respiratory Cell and Molecular Biology (2018)

Jacobo Sellarés Kristen L. Veraldi Katelynn J. Thiel Nayra Cárdenes Diana Álvarez

Idiopathic pulmonary fibrosis (IPF) pathogenesis has been postulated to involve a variety of mechanisms associated with the aging process, including loss of protein homeostasis (proteostasis). Heat shock proteins are cellular chaperones that serve a number of vital maintenance and repair functions, including the regulation of proteostasis. Previously published data have implicated heat shock protein 70 (Hsp70) in the development of pulmonary fibrosis in animal models. We sought to identify alterations in Hsp70 expression in IPF lung. Hsp70 mRNA and protein were decreased in primary fibroblasts cultured from IPF versus normal donor lung tissue. In addition to cultured fibroblasts, Hsp70 expression was decreased in intact IPF lung, a stressed environment in which upregulation of protective heat shock proteins would be anticipated. In support of a mechanistic association between decreased Hsp70 and fibrosis, cultured primary lung fibroblasts deficient in Hsp70 secreted increased extracellular matrix proteins. Treatment of primary normal human lung fibroblasts in vitro with either of the profibrotic molecules IGFBP5 (insulin-like growth factor-binding protein 5) or transforming growth factor-β1 downregulated Hsp70, suggesting Hsp70 is a downstream target in the fibrotic cascade. Hsp70-knockout mice subjected to an inhalational bleomycin model of pulmonary fibrosis demonstrated accelerated fibrosis versus wild-type control animals. We therefore conclude that reduced Hsp70 protein contributes to fibrosis and that interventions aimed at restoring normal expression of Hsp70 represent a novel therapeutic strategy for pulmonary fibrosis.

Proteostasis

10.1165/rcmb.2017-0268oc

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Citations (35)