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1.
EMBO Rep ; 25(3): 1650-1684, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38424230

RESUMEN

Lung diseases develop when telomeres shorten beyond a critical point. We constructed a mouse model in which the catalytic subunit of telomerase (mTert), or its catalytically inactive form (mTertCI), is expressed from the p21Cdkn1a locus. Expression of either TERT or TERTCI reduces global p21 levels in the lungs of aged mice, highlighting TERT non-canonical function. However, only TERT reduces accumulation of very short telomeres, oxidative damage, endothelial cell (ECs) senescence and senile emphysema in aged mice. Single-cell analysis of the lung reveals that p21 (and hence TERT) is expressed mainly in the capillary ECs. We report that a fraction of capillary ECs marked by CD34 and endowed with proliferative capacity declines drastically with age, and this is counteracted by TERT but not TERTCI. Consistently, only TERT counteracts decline of capillary density. Natural aging effects are confirmed using the experimental model of emphysema induced by VEGFR2 inhibition and chronic hypoxia. We conclude that catalytically active TERT prevents exhaustion of the putative CD34 + EC progenitors with age, thus protecting against capillary vessel loss and pulmonary emphysema.


Asunto(s)
Enfisema , Rarefacción Microvascular , Enfisema Pulmonar , Telomerasa , Ratones , Animales , Acortamiento del Telómero , Telomerasa/genética
2.
Circulation ; 147(8): 650-666, 2023 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-36515093

RESUMEN

BACKGROUND: Senescent cells (SCs) are involved in proliferative disorders, but their role in pulmonary hypertension remains undefined. We investigated SCs in patients with pulmonary arterial hypertension and the role of SCs in animal pulmonary hypertension models. METHODS: We investigated senescence (p16, p21) and DNA damage (γ-H2AX, 53BP1) markers in patients with pulmonary arterial hypertension and murine models. We monitored p16 activation by luminescence imaging in p16-luciferase (p16LUC/+) knock-in mice. SC clearance was obtained by a suicide gene (p16 promoter-driven killer gene construct in p16-ATTAC mice), senolytic drugs (ABT263 and cell-permeable FOXO4-p53 interfering peptide [FOXO4-DRI]), and p16 inactivation in p16LUC/LUC mice. We investigated pulmonary hypertension in mice exposed to normoxia, chronic hypoxia, or hypoxia+Sugen, mice overexpressing the serotonin transporter (SM22-5-HTT+), and rats given monocrotaline. RESULTS: Patients with pulmonary arterial hypertension compared with controls exhibited high lung p16, p21, and γ-H2AX protein levels, with abundant vascular cells costained for p16, γ-H2AX, and 53BP1. Hypoxia increased thoracic bioluminescence in p16LUC/+ mice. In wild-type mice, hypoxia increased lung levels of senescence and DNA-damage markers, senescence-associated secretory phenotype components, and p16 staining of pulmonary endothelial cells (P-ECs, 30% of lung SCs in normoxia), and pulmonary artery smooth muscle cells. SC elimination by suicide gene or ABT263 increased the right ventricular systolic pressure and hypertrophy index, increased vessel remodeling (higher dividing proliferating cell nuclear antigen-stained vascular cell counts during both normoxia and hypoxia), and markedly decreased lung P-ECs. Pulmonary hemodynamic alterations and lung P-EC loss occurred in older p16LUC/LUC mice, wild-type mice exposed to Sugen or hypoxia+Sugen, and SM22-5-HTT+ mice given either ABT263 or FOXO4-DRI, compared with relevant controls. The severity of monocrotaline-induced pulmonary hypertension in rats was decreased slightly by ABT263 for 1 week but was aggravated at 3 weeks, with loss of P-ECs. CONCLUSIONS: Elimination of senescent P-ECs by senolytic interventions may worsen pulmonary hemodynamics. These results invite consideration of the potential impact on pulmonary vessels of strategies aimed at controlling cell senescence in various contexts.


Asunto(s)
Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Ratones , Ratas , Animales , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/metabolismo , Células Endoteliales/metabolismo , Monocrotalina/metabolismo , Senoterapéuticos , Arteria Pulmonar , Hipertensión Pulmonar Primaria Familiar/metabolismo , Hipoxia/metabolismo , Senescencia Celular , Factores de Transcripción Forkhead/metabolismo
3.
Circulation ; 144(7): 559-574, 2021 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-34162223

RESUMEN

BACKGROUND: Aging myocardium undergoes progressive cardiac hypertrophy and interstitial fibrosis with diastolic and systolic dysfunction. Recent metabolomics studies shed light on amino acids in aging. The present study aimed to dissect how aging leads to elevated plasma levels of the essential amino acid phenylalanine and how it may promote age-related cardiac dysfunction. METHODS: We studied cardiac structure and function, together with phenylalanine catabolism in wild-type (WT) and p21-/- mice (male; 2-24 months), with the latter known to be protected from cellular senescence. To explore phenylalanine's effects on cellular senescence and ectopic phenylalanine catabolism, we treated cardiomyocytes (primary adult rat or human AC-16) with phenylalanine. To establish a role for phenylalanine in driving cardiac aging, WT male mice were treated twice a day with phenylalanine (200 mg/kg) for a month. We also treated aged WT mice with tetrahydrobiopterin (10 mg/kg), the essential cofactor for the phenylalanine-degrading enzyme PAH (phenylalanine hydroxylase), or restricted dietary phenylalanine intake. The impact of senescence on hepatic phenylalanine catabolism was explored in vitro in AML12 hepatocytes treated with Nutlin3a (a p53 activator), with or without p21-targeting small interfering RNA or tetrahydrobiopterin, with quantification of PAH and tyrosine levels. RESULTS: Natural aging is associated with a progressive increase in plasma phenylalanine levels concomitant with cardiac dysfunction, whereas p21 deletion delayed these changes. Phenylalanine treatment induced premature cardiac deterioration in young WT mice, strikingly akin to that occurring with aging, while triggering cellular senescence, redox, and epigenetic changes. Pharmacological restoration of phenylalanine catabolism with tetrahydrobiopterin administration or dietary phenylalanine restriction abrogated the rise in plasma phenylalanine and reversed cardiac senescent alterations in aged WT mice. Observations from aged mice and human samples implicated age-related decline in hepatic phenylalanine catabolism as a key driver of elevated plasma phenylalanine levels and showed increased myocardial PAH-mediated phenylalanine catabolism, a novel signature of cardiac aging. CONCLUSIONS: Our findings establish a pathogenic role for increased phenylalanine levels in cardiac aging, linking plasma phenylalanine levels to cardiac senescence via dysregulated phenylalanine catabolism along a hepatic-cardiac axis. They highlight phenylalanine/PAH modulation as a potential therapeutic strategy for age-associated cardiac impairment.


Asunto(s)
Envejecimiento/metabolismo , Miocardio/metabolismo , Fenilalanina/metabolismo , Envejecimiento/patología , Aminoácidos/metabolismo , Animales , Biomarcadores , Biopterinas/análogos & derivados , Biopterinas/farmacología , Catálisis , Senescencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Cardiopatías/etiología , Cardiopatías/metabolismo , Cardiopatías/patología , Cardiopatías/fisiopatología , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Noqueados , Modelos Biológicos , Miocardio/patología , Miocitos Cardíacos/metabolismo , Fenilalanina/sangre , Ratas
4.
Eur Respir J ; 58(2)2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33509955

RESUMEN

BACKGROUND: Cell senescence is a key process in age-associated dysfunction and diseases, notably chronic obstructive pulmonary disease (COPD). We previously identified phospholipase A2 receptor 1 (PLA2R1) as a positive regulator of cell senescence acting via Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling. Its role in pathology, however, remains unknown. Here, we assessed PLA2R1-induced senescence in COPD and lung emphysema pathogenesis. METHODS: We assessed cell senescence in lungs and cultured lung cells from patients with COPD and controls subjected to PLA2R1 knockdown, PLA2R1 gene transduction and treatment with the JAK1/2 inhibitor ruxolitinib. To assess whether PLA2R1 upregulation caused lung lesions, we developed transgenic mice overexpressing PLA2R1 (PLA2R1-TG) and intratracheally injected wild-type mice with a lentiviral vector carrying the Pla2r1 gene (LV-PLA2R1 mice). RESULTS: We found that PLA2R1 was overexpressed in various cell types exhibiting senescence characteristics in COPD lungs. PLA2R1 knockdown extended the population doubling capacity of these cells and inhibited their pro-inflammatory senescence-associated secretory phenotype (SASP). PLA2R1-mediated cell senescence in COPD was largely reversed by treatment with the potent JAK1/2 inhibitor ruxolitinib. Five-month-old PLA2R1-TG mice exhibited lung cell senescence, and developed lung emphysema and lung fibrosis together with pulmonary hypertension. Treatment with ruxolitinib induced reversal of lung emphysema and fibrosis. LV-PLA2R1-treated mice developed lung emphysema within 4 weeks and this was markedly attenuated by concomitant ruxolitinib treatment. CONCLUSIONS: Our data support a major role for PLA2R1 activation in driving lung cell senescence and lung alterations in COPD. Targeting JAK1/2 may represent a promising therapeutic approach for COPD.


Asunto(s)
Enfisema , Enfermedad Pulmonar Obstructiva Crónica , Enfisema Pulmonar , Animales , Senescencia Celular , Humanos , Pulmón , Ratones , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Receptores de Fosfolipasa A2
5.
Am J Respir Crit Care Med ; 202(8): 1088-1104, 2020 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-32628504

RESUMEN

Rationale: Promoting endogenous pulmonary regeneration is crucial after damage to restore normal lungs and prevent the onset of chronic adult lung diseases.Objectives: To investigate whether the cell-cycle inhibitor p16INK4a limits lung regeneration after newborn bronchopulmonary dysplasia (BPD), a condition characterized by the arrest of alveolar development, leading to adult sequelae.Methods: We exposed p16INK4a-/- and p16INK4aATTAC (apoptosis through targeted activation of caspase 8) transgenic mice to postnatal hyperoxia, followed by pneumonectomy of the p16INK4a-/- mice. We measured p16INK4a in blood mononuclear cells of preterm newborns, 7- to 15-year-old survivors of BPD, and the lungs of patients with BPD.Measurements and Main Results: p16INK4a concentrations increased in lung fibroblasts after hyperoxia-induced BPD in mice and persisted into adulthood. p16INK4a deficiency did not protect against hyperoxic lesions in newborn pups but promoted restoration of the lung architecture by adulthood. Curative clearance of p16INK4a-positive cells once hyperoxic lung lesions were established restored normal lungs by adulthood. p16INK4a deficiency increased neutral lipid synthesis and promoted lipofibroblast and alveolar type 2 (AT2) cell development within the stem-cell niche. Besides, lipofibroblasts support self-renewal of AT2 cells into alveolospheres. Induction with a PPARγ (peroxisome proliferator-activated receptor γ) agonist after hyperoxia also increased lipofibroblast and AT2 cell numbers and restored alveolar architecture in hyperoxia-exposed mice. After pneumonectomy, p16INK4a deficiency again led to an increase in lipofibroblast and AT2 cell numbers in the contralateral lung. Finally, we observed p16INK4a mRNA overexpression in the blood and lungs of preterm newborns, which persisted in the blood of older survivors of BPD.Conclusions: These data demonstrate the potential of targeting p16INK4a and promoting lipofibroblast development to stimulate alveolar regeneration from childhood to adulthood.


Asunto(s)
Displasia Broncopulmonar/patología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Fibroblastos/metabolismo , Pulmón/fisiología , Regeneración/fisiología , Adolescente , Adulto , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/patología , Animales , Animales Recién Nacidos , Apoptosis , Displasia Broncopulmonar/metabolismo , Células Cultivadas , Niño , Modelos Animales de Enfermedad , Fibroblastos/patología , Humanos , Hiperoxia/complicaciones , Hiperoxia/metabolismo , Hiperoxia/patología , Recién Nacido , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Alveolos Pulmonares/patología , Distribución Aleatoria , Muestreo , Adulto Joven
6.
Eur Respir J ; 54(4)2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31320454

RESUMEN

Macrophages are major players in the pathogenesis of pulmonary arterial hypertension (PAH).To investigate whether lung macrophages and pulmonary-artery smooth muscle cells (PASMCs) collaborate to stimulate PASMC growth and whether the CCL2-CCR2 and CCL5-CCR5 pathways inhibited macrophage-PASMC interactions and PAH development, we used human CCR5-knock-in mice and PASMCs from patients with PAH and controls.Conditioned media from murine M1 or M2 macrophages stimulated PASMC growth. This effect was markedly amplified with conditioned media from M2 macrophage/PASMC co-cultures. CCR2, CCR5, CCL2 and CCL5 were upregulated in macrophage/PASMC co-cultures. Compared to inhibiting either receptor, dual CCR2 and CCR5 inhibition more strongly attenuated the growth-promoting effect of conditioned media from M2-macrophage/PASMC co-cultures. Deleting either CCR2 or CCR5 in macrophages or PASMCs attenuated the growth response. In mice with hypoxia- or SUGEN/hypoxia-induced PH, targeting both CCR2 and CCR5 prevented or reversed PH more efficiently than targeting either receptor alone. Patients with PAH exhibited CCR2 and CCR5 upregulation in PASMCs and perivascular macrophages compared to controls. The PASMC growth-promoting effect of conditioned media from M2-macrophage/PASMC co-cultures was greater when PASMCs from PAH patients were used in the co-cultures or as the target cells and was dependent on CCR2 and CCR5. PASMC migration toward M2-macrophages was greater with PASMCs from PAH patients and was attenuated by blocking CCR2 and CCR5.CCR2 and CCR5 are required for collaboration between macrophages and PASMCs to initiate and amplify PASMC migration and proliferation during PAH development. Dual targeting of CCR2 and CCR5 may hold promise for treating human PAH.


Asunto(s)
Macrófagos/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Hipertensión Arterial Pulmonar/metabolismo , Receptores CCR2/metabolismo , Receptores CCR5/metabolismo , Adolescente , Adulto , Animales , Comunicación Celular , Movimiento Celular/genética , Proliferación Celular/genética , Técnicas de Cocultivo , Medios de Cultivo Condicionados , Modelos Animales de Enfermedad , Femenino , Técnicas de Sustitución del Gen , Humanos , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Músculo Liso Vascular/citología , Hipertensión Arterial Pulmonar/genética , Arteria Pulmonar/citología , Arteria Pulmonar/metabolismo , Receptores CCR2/genética , Receptores CCR5/genética , Adulto Joven
7.
J Cardiovasc Pharmacol ; 71(5): 283-292, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29438213

RESUMEN

Nitric oxide (NO) donors may be useful for treating pulmonary hypertension (PH) complicating sickle cell disease (SCD), as endogenous NO is inactivated by hemoglobin released by intravascular hemolysis. Here, we investigated the effects of the new NO donor NCX1443 on PH in transgenic SAD mice, which exhibit mild SCD without severe hemolytic anemia. In SAD and wild-type (WT) mice, the pulmonary pressure response to acute hypoxia was similar and was abolished by 100 mg/kg NCX1443. The level of PH was also similar in SAD and WT mice exposed to chronic hypoxia (9% O2) alone or with SU5416 and was similarly reduced by daily NCX1443 gavage. Compared with WT mice, SAD mice exhibited higher levels of HO-1, endothelial NO synthase, and PDE5 but similar levels of lung cyclic guanosine monophosphate. Cultured pulmonary artery smooth muscle cells from SAD mice grew faster than those from WT mice and had higher PDE5 protein levels. Combining NCX1443 and a PDE5 inhibitor suppressed the growth rate difference between SAD and WT cells and induced a larger reduction in hypoxic PH severity in SAD than in WT mice. By amplifying endogenous protective mechanisms, NCX1443 in combination with PDE5 inhibition may prove useful for treating PH complicating SCD.


Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Antihipertensivos/farmacología , Presión Arterial/efectos de los fármacos , Hipertensión Pulmonar/prevención & control , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico/metabolismo , Arteria Pulmonar/efectos de los fármacos , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/metabolismo , Animales , Antihipertensivos/metabolismo , Proliferación Celular/efectos de los fármacos , Células Cultivadas , GMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Modelos Animales de Enfermedad , Hemo-Oxigenasa 1/metabolismo , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Hipoxia/complicaciones , Masculino , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Ratones Transgénicos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Donantes de Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Inhibidores de Fosfodiesterasa 5/farmacología , Arteria Pulmonar/metabolismo , Arteria Pulmonar/fisiopatología
8.
Eur Respir J ; 48(2): 470-83, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27418552

RESUMEN

Pulmonary artery smooth muscle cell (PA-SMC) proliferation and inflammation are key components of pulmonary arterial hypertension (PAH). Interleukin (IL)-1ß binds to IL-1 receptor (R)1, thereby recruiting the molecular adaptor myeloid differentiation primary response protein 88 (MyD88) (involved in IL-1R1 and Toll-like receptor signal transduction) and inducing IL-1, IL-6 and tumour necrosis factor-α synthesis through nuclear factor-κB activation.We investigated the IL-1R1/MyD88 pathway in the pathogenesis of pulmonary hypertension.Marked IL-1R1 and MyD88 expression with predominant PA-SMC immunostaining was found in lungs from patients with idiopathic PAH, mice with hypoxia-induced pulmonary hypertension and SM22-5-HTT(+) mice. Elevations in lung IL-1ß, IL-1R1, MyD88 and IL-6 preceded pulmonary hypertension in hypoxic mice. IL-1R1(-/-), MyD88(-/-) and control mice given the IL-1R1 antagonist anakinra were protected similarly against hypoxic pulmonary hypertension and perivascular macrophage recruitment. Anakinra reversed pulmonary hypertension partially in SM22-5-HTT(+) mice and markedly in monocrotaline-treated rats. IL-1ß-mediated stimulation of mouse PA-SMC growth was abolished by anakinra and absent in IL-1R1(-/-) and MyD88(-/-) mice. Gene deletion confined to the myeloid lineage (M.lys-Cre MyD88(fl/fl) mice) decreased pulmonary hypertension severity versus controls, suggesting IL-1ß-mediated effects on PA-SMCs and macrophages. The growth-promoting effect of media conditioned by M1 or M2 macrophages from M.lys-Cre MyD88(fl/fl) mice was attenuated.Pulmonary vessel remodelling and inflammation during pulmonary hypertension require IL-1R1/MyD88 signalling. Targeting the IL-1ß/IL-1R1 pathway may hold promise for treating human PAH.


Asunto(s)
Hipertensión Pulmonar/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Receptores Tipo I de Interleucina-1/metabolismo , Transducción de Señal , Animales , Diferenciación Celular , Proliferación Celular , Medios de Cultivo Condicionados/química , Eliminación de Gen , Humanos , Inflamación , Proteína Antagonista del Receptor de Interleucina 1/química , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Monocrotalina/química , Miocitos del Músculo Liso/metabolismo , FN-kappa B/metabolismo , Ratas , Ratas Wistar
10.
JCI Insight ; 8(8)2023 04 24.
Artículo en Inglés | MEDLINE | ID: mdl-37092554

RESUMEN

Adipose tissue macrophages (ATMs) play an important role in obesity and inflammation, and they accumulate in adipose tissue (AT) with aging. Furthermore, increased ATM senescence has been shown in obesity-related AT remodeling and dysfunction. However, ATM senescence and its role are unclear in age-related AT dysfunction. Here, we show that ATMs (a) acquire a senescence-like phenotype during chronological aging; (b) display a global decline of basic macrophage functions such as efferocytosis, an essential process to preserve AT homeostasis by clearing dysfunctional or apoptotic cells; and (c) promote AT remodeling and dysfunction. Importantly, we uncover a major role for the age-associated accumulation of osteopontin (OPN) in these processes in visceral AT. Consistently, loss or pharmacologic inhibition of OPN and bone marrow transplantation of OPN-/- mice attenuate the ATM senescence-like phenotype, preserve efferocytosis, and finally restore healthy AT homeostasis in the context of aging. Collectively, our findings implicate pharmacologic OPN inhibition as a viable treatment modality to counter ATM senescence-mediated AT remodeling and dysfunction during aging.


Asunto(s)
Obesidad , Osteopontina , Ratones , Animales , Osteopontina/genética , Obesidad/genética , Tejido Adiposo , Macrófagos , Fagocitosis
11.
Cell Rep ; 41(11): 111810, 2022 12 13.
Artículo en Inglés | MEDLINE | ID: mdl-36516767

RESUMEN

Multiciliated ependymal cells and adult neural stem cells are components of the adult neurogenic niche, essential for brain homeostasis. These cells share a common glial cell lineage regulated by the Geminin family members Geminin and GemC1/Mcidas. Ependymal precursors require GemC1/Mcidas expression to massively amplify centrioles and become multiciliated cells. Here, we show that GemC1-dependent differentiation is initiated in actively cycling radial glial cells, in which a DNA damage response, including DNA replication-associated damage and dysfunctional telomeres, is induced, without affecting cell survival. Genotoxic stress is not sufficient by itself to induce ependymal cell differentiation, although the absence of p53 or p21 in progenitors hinders differentiation by maintaining cell division. Activation of the p53-p21 pathway downstream of GemC1 leads to cell-cycle slowdown/arrest, which permits timely onset of ependymal cell differentiation in progenitor cells.


Asunto(s)
Células-Madre Neurales , Proteína p53 Supresora de Tumor , Geminina/genética , Geminina/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Epéndimo/metabolismo , Células Ependimogliales/metabolismo , Células-Madre Neurales/metabolismo , Diferenciación Celular
12.
JCI Insight ; 4(19)2019 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-31578304

RESUMEN

Oxidative stress is a major contributor to chronic lung diseases. Antioxidants such as N-acetylcysteine (NAC) are broadly viewed as protective molecules that prevent the mutagenic effects of reactive oxygen species. Antioxidants may, however, increase the risk of some forms of cancer and accelerate lung cancer progression in murine models. Here, we investigated chronic NAC treatment in aging mice displaying lung oxidative stress and cell senescence due to inactivation of the transcription factor JunD, which is downregulated in diseased human lungs. NAC treatment decreased lung oxidative damage and cell senescence and protected from lung emphysema but concomitantly induced the development of lung adenocarcinoma in 50% of JunD-deficient mice and 10% of aged control mice. This finding constitutes the first evidence to our knowledge of a carcinogenic effect of antioxidant therapy in the lungs of aged mice with chronic lung oxidative stress and warrants the utmost caution when considering the therapeutic use of antioxidants.


Asunto(s)
Acetilcisteína/efectos adversos , Acetilcisteína/farmacología , Adenocarcinoma del Pulmón/inducido químicamente , Antioxidantes/efectos adversos , Antioxidantes/farmacología , Enfisema Pulmonar/tratamiento farmacológico , Adenocarcinoma del Pulmón/patología , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Pulmón/patología , Enfermedades Pulmonares/patología , Neoplasias Pulmonares , Masculino , Ratones , Ratones Noqueados , Estrés Oxidativo/efectos de los fármacos , Proteínas Proto-Oncogénicas c-jun/genética , Enfisema Pulmonar/patología , Especies Reactivas de Oxígeno
13.
JCI Insight ; 3(3)2018 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-29415880

RESUMEN

Chronic obstructive pulmonary disease (COPD) is a highly prevalent and devastating condition for which no curative treatment is available. Exaggerated lung cell senescence may be a major pathogenic factor. Here, we investigated the potential role for mTOR signaling in lung cell senescence and alterations in COPD using lung tissue and derived cultured cells from patients with COPD and from age- and sex-matched control smokers. Cell senescence in COPD was linked to mTOR activation, and mTOR inhibition by low-dose rapamycin prevented cell senescence and inhibited the proinflammatory senescence-associated secretory phenotype. To explore whether mTOR activation was a causal pathogenic factor, we developed transgenic mice exhibiting mTOR overactivity in lung vascular cells or alveolar epithelial cells. In this model, mTOR activation was sufficient to induce lung cell senescence and to mimic COPD lung alterations, with the rapid development of lung emphysema, pulmonary hypertension, and inflammation. These findings support a causal relationship between mTOR activation, lung cell senescence, and lung alterations in COPD, thereby identifying the mTOR pathway as a potentially new therapeutic target in COPD.


Asunto(s)
Pulmón/patología , Enfermedad Pulmonar Obstructiva Crónica/patología , Enfisema Pulmonar/patología , Serina-Treonina Quinasas TOR/metabolismo , Anciano , Animales , Estudios de Casos y Controles , Células Cultivadas , Senescencia Celular/efectos de los fármacos , Femenino , Humanos , Pulmón/citología , Pulmón/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Cultivo Primario de Células , Enfisema Pulmonar/genética , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/genética , Fumar Tabaco/patología , Proteína 1 del Complejo de la Esclerosis Tuberosa/deficiencia , Proteína 1 del Complejo de la Esclerosis Tuberosa/genética
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