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1.
J Cell Sci ; 135(5)2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-34080635

RESUMO

Despite the recognized significance of reversible protein lipidation (S-acylation) for T cell receptor signal transduction, the enzymatic control of this post-translational modification in T cells remains poorly understood. Here, we demonstrate that DHHC21 (also known as ZDHHC21), a member of the DHHC family of mammalian protein acyltransferases, mediates T cell receptor-induced S-acylation of proximal T cell signaling proteins. Using Zdhhc21dep mice, which express a functionally deficient version of DHHC21, we show that DHHC21 is a Ca2+/calmodulin-dependent enzyme critical for activation of naïve CD4+ T cells in response to T cell receptor stimulation. We find that disruption of the Ca2+/calmodulin-binding domain of DHHC21 does not affect thymic T cell development but prevents differentiation of peripheral CD4+ T cells into Th1, Th2 and Th17 effector T helper lineages. Our findings identify DHHC21 as an essential component of the T cell receptor signaling machinery and define a new role for protein acyltransferases in regulation of T cell-mediated immunity.

3.
J Exp Med ; 218(6)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-33891683

RESUMO

Previous studies implicated the neuronal guidance molecule netrin-1 in attenuating myocardial ischemia-reperfusion injury. However, the tissue-specific sources and receptor signaling events remain elusive. Neutrophils are among the first cells responding to an ischemic insult and can be associated with tissue injury or rescue. We found netrin-1 levels were elevated in the blood of patients with myocardial infarction, as well as in mice exposed to myocardial ischemia-reperfusion. Selectively increased infarct sizes and troponin levels were found in Ntn1loxP/loxP Lyz2 Cre+ mice, but not in mice with conditional netrin-1 deletion in other tissue compartments. In vivo studies using neutrophil depletion identified neutrophils as the main source for elevated blood netrin-1 during myocardial injury. Finally, pharmacologic studies using treatment with recombinant netrin-1 revealed a functional role for purinergic signaling events through the myeloid adenosine A2b receptor in mediating netrin-1-elicited cardioprotection. These findings suggest an autocrine signaling loop with a functional role for neutrophil-derived netrin-1 in attenuating myocardial ischemia-reperfusion injury through myeloid adenosine A2b signaling.

4.
FASEB J ; 35(4): e21334, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33715200

RESUMO

Sepsis and sepsis-associated lung inflammation significantly contribute to the morbidity and mortality of critical illness. Here, we examined the hypothesis that neuronal guidance proteins could orchestrate inflammatory events during endotoxin-induced lung injury. Through a targeted array, we identified netrin-1 as the top upregulated neuronal guidance protein in macrophages treated with lipopolysaccharide (LPS). Furthermore, we found that netrin-1 is highly enriched in infiltrating myeloid cells, particularly in macrophages during LPS-induced lung injury. Transcriptional studies implicate hypoxia-inducible factor HIF-1α in the transcriptional induction of netrin-1 during LPS treatment. Subsequently, the deletion of netrin-1 in the myeloid compartment (Ntn1loxp/loxp LysM Cre) resulted in exaggerated mortality and lung inflammation. Surprisingly, further studies revealed enhanced natural killer cells (NK cells) infiltration in Ntn1loxp/loxp LysM Cre mice, and neutralization of NK cell chemoattractant chemokine (C-C motif) ligand 2 (CCL2) reversed the exaggerated lung inflammation. Together, these studies provide functional insight into myeloid cell-derived netrin-1 in controlling lung inflammation through the modulation of CCL2-dependent infiltration of NK cells.

5.
Front Immunol ; 11: 604944, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33519814

RESUMO

Hypoxia and inflammation often coincide in pathogenic conditions such as acute respiratory distress syndrome (ARDS) and chronic lung diseases, which are significant contributors to morbidity and mortality for the general population. For example, the recent global outbreak of Coronavirus disease 2019 (COVID-19) has placed viral infection-induced ARDS under the spotlight. Moreover, chronic lung disease ranks the third leading cause of death in the United States. Hypoxia signaling plays a diverse role in both acute and chronic lung inflammation, which could partially be explained by the divergent function of downstream target pathways such as adenosine signaling. Particularly, hypoxia signaling activates adenosine signaling to inhibit the inflammatory response in ARDS, while in chronic lung diseases, it promotes inflammation and tissue injury. In this review, we discuss the role of adenosine at the interphase of hypoxia and inflammation in ARDS and chronic lung diseases, as well as the current strategy for therapeutic targeting of the adenosine signaling pathway.


Assuntos
Adenosina/metabolismo , Hipóxia/metabolismo , Inflamação/metabolismo , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/terapia , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/etiologia , Terapia de Alvo Molecular , Receptores Purinérgicos P1/metabolismo , /metabolismo , /terapia , Transdução de Sinais
6.
J Biol Chem ; 294(43): 15781-15794, 2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31488543

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterized by the pathological remodeling of air sacs as a result of excessive accumulation of extracellular matrix (ECM) proteins, but the mechanism governing the robust protein expression is poorly understood. Our recent findings demonstrate that alternative polyadenylation (APA) caused by NUDT21 reduction is important for the increased expression of fibrotic mediators and ECM proteins in lung fibroblasts by shortening the 3'-untranslated regions (3'-UTRs) of mRNAs and stabilizing their transcripts, therefore activating pathological signaling pathways. Despite the importance of NUDT21 reduction in the regulation of fibrosis, the underlying mechanisms for the depletion are unknown. We demonstrate here that NUDT21 is depleted by TGFß1. We found that miR203, which is increased in IPF, was induced by TGFß1 to target the NUDT21 3'-UTR, thus depleting NUDT21 in human and mouse lung fibroblasts. TGFß1-mediated NUDT21 reduction was attenuated by the miR203 inhibitor antagomiR203 in fibroblasts. TGFß1 transgenic mice revealed that TGFß1 down-regulates NUDT21 in fibroblasts in vivo Furthermore, TGFß1 promoted differential APA of fibrotic genes, including FGF14, RICTOR, TMOD2, and UCP5, in association with increased protein expression. This unique differential APA signature was also observed in IPF fibroblasts. Altogether, our results identified TGFß1 as an APA regulator through NUDT21 depletion amplifying pulmonary fibrosis.


Assuntos
Regiões 3' não Traduzidas/genética , Pulmão/patologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Células Cultivadas , Fator de Especificidade de Clivagem e Poliadenilação/genética , Fator de Especificidade de Clivagem e Poliadenilação/metabolismo , Regulação para Baixo/genética , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Humanos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , MicroRNAs/genética , MicroRNAs/metabolismo , Modelos Biológicos , Poliadenilação/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
7.
Genome Med ; 11(1): 55, 2019 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-31446897

RESUMO

BACKGROUND: Human cancer cell lines are fundamental models for cancer research and therapeutic strategy development. However, there is no characterization of circular RNAs (circRNAs) in a large number of cancer cell lines. METHODS: Here, we apply four circRNA identification algorithms to heuristically characterize the expression landscape of circRNAs across ~ 1000 human cancer cell lines from CCLE polyA-enriched RNA-seq data. By using integrative analysis and experimental approaches, we explore the expression landscape, biogenesis, functional consequences, and drug response of circRNAs across different cancer lineages. RESULTS: We revealed highly lineage-specific expression patterns of circRNAs, suggesting that circRNAs may be powerful diagnostic and/or prognostic markers in cancer treatment. We also identified key genes involved in circRNA biogenesis and confirmed that TGF-ß signaling may promote biogenesis of circRNAs. Strikingly, we showed that clinically actionable genes are more likely to generate circRNAs, potentially due to the enrichment of RNA-binding protein (RBP) binding sites. Among these, circMYC can promote cell proliferation. We observed strong association between the expression of circRNAs and the response to drugs, especially those targeting chromatin histone acetylation. Finally, we developed a user-friendly data portal, CircRNAs in cancer cell lines (CircRiC, https://hanlab.uth.edu/cRic ), to benefit the biomedical research community. CONCLUSIONS: Our study provides the characterization of circRNAs in cancer cell lines and explored the potential mechanism of circRNA biogenesis as well as its therapeutic implications. We also provide a data portal to facilitate the related biomedical researches.


Assuntos
Neoplasias/genética , RNA Circular , Linhagem Celular Tumoral , Biologia Computacional , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Transcriptoma
8.
Ann Rheum Dis ; 78(11): 1583-1591, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31439591

RESUMO

OBJECTIVES: There is considerable evidence that implicates dysregulation of type I interferon signalling (or type I IFN signature) in the pathogenesis of systemic sclerosis (SSc). Interferon regulatory factor 7 (IRF7) has been recognised as a master regulator of type I IFN signalling. The objective of this study was to elucidate the role of IRF7 in dermal fibrosis and SSc pathogenesis. METHODS: SSc and healthy control skin biopsies were investigated to determine IRF7 expression and activation. The role of IRF7 in fibrosis was investigated using IRF7 knockout (KO) mice in the bleomycin-induced and TSK/+mouse models. In vitro experiments with dermal fibroblasts from patients with SSc and healthy controls were performed. RESULTS: IRF7 expression was significantly upregulated and activated in SSc skin tissue and explanted SSc dermal fibroblasts compared with unaffected, matched controls. Moreover, IRF7 expression was stimulated by IFN-α in dermal fibroblasts. Importantly, IRF7 co-immunoprecipitated with Smad3, a key mediator of transforming growth factor (TGF)-ß signalling, and IRF7 knockdown reduced profibrotic factors in SSc fibroblasts. IRF7 KO mice demonstrated attenuated dermal fibrosis and inflammation compared with wild-type mice in response to bleomycin. Specifically, hydroxyproline content, dermal thickness as well as Col1a2, ACTA2 and interleukin-6 mRNA levels were significantly attenuated in IRF7 KO mice skin tissue. Furthermore, IRF7 KO in TSK/+mice attenuated hydroxyproline content, subcutaneous hypodermal thickness, Col1a2 mRNA as well as α-smooth muscle actin and fibronectin expression. CONCLUSIONS: IRF7 is upregulated in SSc skin, interacts with Smad3 and potentiates TGF-ß-mediated fibrosis, and therefore may represent a promising therapeutic target in SSc.


Assuntos
Inflamação/genética , Fator Regulador 7 de Interferon/metabolismo , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/patologia , Pele/patologia , Animais , Bleomicina , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibrose , Humanos , Camundongos , Camundongos Knockout , Escleroderma Sistêmico/induzido quimicamente , Transdução de Sinais/genética , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Regulação para Cima
9.
JCI Insight ; 3(20)2018 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-30333323

RESUMO

Intestinal epithelial barrier repair is vital for remission in inflammatory bowel disease (IBD). Extracellular adenosine signaling has been implicated in promoting restoration of epithelial barrier function. Currently, no clinically approved agents target this pathway. Adenosine signaling is terminated by uptake from the extracellular space via equilibrative nucleoside transporters (ENTs). We hypothesized that ENT inhibition could dampen intestinal inflammation. Initial studies demonstrated transcriptional repression of ENT1 and ENT2 in IBD biopsies or in murine IBD models. Subsequent studies in mice with global Ent1 or Ent2 deletion revealed selective protection of Ent2-/- mice. Elevated intestinal adenosine levels in conjunction with abolished protection following pharmacologic blockade of A2B adenosine receptors implicate adenosine signaling as the mechanism of gut protection in Ent2-/- mice. Additional studies in mice with tissue-specific deletion of Ent2 uncovered epithelial Ent2 as the target. Moreover, intestinal protection provided by a selective Ent2 inhibitor was abolished in mice with epithelium-specific deletion of Ent2 or the A2B adenosine receptor. Taken together, these findings indicate that increased mucosal A2B signaling following repression or deletion of epithelial Ent2 coordinates the resolution of intestinal inflammation. This study suggests the presence of a targetable purinergic network within the intestinal epithelium designed to limit tissue inflammation.


Assuntos
Colite Ulcerativa/patologia , Doença de Crohn/patologia , Transportador Equilibrativo 2 de Nucleosídeo/metabolismo , Mucosa Intestinal/patologia , Receptor A2B de Adenosina/metabolismo , Adenosina/metabolismo , Antagonistas do Receptor A2 de Adenosina/administração & dosagem , Animais , Biópsia , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/imunologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Doença de Crohn/imunologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Transportador Equilibrativo 1 de Nucleosídeo/genética , Transportador Equilibrativo 1 de Nucleosídeo/metabolismo , Transportador Equilibrativo 2 de Nucleosídeo/antagonistas & inibidores , Transportador Equilibrativo 2 de Nucleosídeo/genética , Feminino , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Masculino , Camundongos , Camundongos Knockout , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
10.
Physiol Rep ; 6(6): e13648, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29595879

RESUMO

Severe acute respiratory distress syndrome (ARDS) presents typically with an initializing event, followed by the need for mechanical ventilation. Most animal models of ALI are limited by the fact that they focus on a singular cause of acute lung injury (ALI) and therefore fail to mimic the complex, multifactorial pathobiology of ARDS. To better capture this scenario, we provide a comprehensive characterization of models of ALI combining two injuries: intra tracheal (i.t.) instillation of LPS or hypochloric acid (HCl) followed by ventilator-induced lung injury (VILI). We hypothesized, that mice pretreated with LPS or HCl prior to VILI and thus receiving a ("two-hit injury") will sustain a superadditive lung injury when compared to VILI. Mice were allocated to following treatment groups: control with i.t. NaCl, ventilation with low peak inspiratory pressure (PIP), i.t. HCl, i.t. LPS, VILI (high PIP), HCl i.t. followed by VILI and LPS i.t. followed by VILI. Severity of injury was determined by protein content and MPO activity in bronchoalveolar lavage (BAL), the expression of inflammatory cytokines and histopathology. Mice subjected to VILI after HCl or LPS instillation displayed augmented lung injury, compared to singular lung injury. However, mice that received i.t. LPS prior to VILI showed significantly increased inflammatory lung injury compared to animals that underwent i.t. HCl followed by VILI. The two-hit lung injury models described, resulting in additive but differential acute lung injury recaptures the clinical relevant multifactorial etiology of ALI and could be a valuable tool in translational research.


Assuntos
Modelos Animais de Doenças , Animais , Feminino , Ácido Clorídrico/toxicidade , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , /fisiopatologia , Lesão Pulmonar Induzida por Ventilação Mecânica/complicações
11.
J Natl Cancer Inst ; 110(4): 379-389, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29106591

RESUMO

Background: Alternative polyadenylation (APA) is emerging as a major post-transcriptional mechanism for gene regulation, and dysregulation of APA contributes to several human diseases. However, the functional consequences of APA in human cancer are not fully understood. Particularly, there is no large-scale analysis in cancer cell lines. Methods: We characterized the global APA profiles of 6398 patient samples across 17 cancer types from The Cancer Genome Atlas and 739 cancer cell lines from the Cancer Cell Line Encyclopedia. We built a linear regression model to explore the correlation between APA factors and APA events across different cancer types. We used Spearman correlation to assess the effects of APA events on drug sensitivity and the Wilcoxon rank-sum test or Cox proportional hazards model to identify clinically relevant APA events. Results: We revealed a striking global 3'UTR shortening in cancer cell lines compared with tumor samples. Our analysis further suggested PABPN1 as the master regulator in regulating APA profile across different cancer types. Furthermore, we showed that APA events could affect drug sensitivity, especially of drugs targeting chromatin modifiers. Finally, we identified 1971 clinically relevant APA events, as well as alterations of APA in clinically actionable genes, suggesting that analysis of the complexity of APA profiles could have clinical utility. Conclusions: Our study highlights important roles for APA in human cancer, including reshaping cellular pathways and regulating specific gene expression, exemplifying the complex interplay between APA and other biological processes and yielding new insights into the action mechanism of cancer drugs.


Assuntos
Regiões 3' não Traduzidas , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Proteína I de Ligação a Poli(A)/genética , Poliadenilação , RNA Mensageiro/genética , Seguimentos , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias/patologia , Prognóstico , Células Tumorais Cultivadas
12.
Pediatr Res ; 2017 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-28832580

RESUMO

BackgroundHyperoxic lung injury is characterized by cellular damage from high oxygen concentrations that lead to an inflammatory response and it disrupts normal alveolarization in the developing newborn lung. Adenosine is a signaling molecule that is generated extracellularly by ecto-5'-nucleotidase (CD73) in response to injury. Extracellular adenosine signals through cell surface receptors and has been found to have a protective role in acute injury situations; however, chronic elevations have been associated with detrimental changes in chronic lung diseases. We hypothesized that hyperoxia-induced lung injury leads to CD73-mediated increases in extracellular adenosine, which are detrimental to the newborn lung.MethodsC57Bl/6 and CD73-/- mice were exposed to 95% oxygen, 70% oxygen, or room air. Adenosine concentration and markers of pulmonary inflammation and lung development were measured.ResultsExposure to hyperoxia caused pulmonary inflammation and disrupted normal alveolar development in association with increased pulmonary adenosine levels. Loss of CD73-mediated extracellular adenosine production led to decreased survival with exposure to 95% oxygen, and exacerbated pulmonary inflammation and worsened lung development with 70% oxygen exposure.ConclusionExposure to hyperoxia causes lung injury associated with an increase in adenosine concentration, and loss of CD73-mediated adenosine production leads to worsening of hyperoxic lung injury.Pediatric Research advance online publication, 23 August 2017; doi:10.1038/pr.2017.176.

13.
FASEB J ; 31(11): 4745-4758, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28701304

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a deadly chronic lung disease. Extracellular accumulation of adenosine and subsequent activation of the ADORA2B receptor play important roles in regulating inflammation and fibrosis in IPF. Additionally, alternatively activated macrophages (AAMs) expressing ADORA2B have been implicated in mediating adenosine's effects in IPF. Although hypoxic conditions are present in IPF, hypoxia's role as a direct modulator of macrophage phenotype and identification of factors that regulate ADORA2B expression on AAMs in IPF is not well understood. In this study, an experimental mouse model of pulmonary fibrosis and lung samples from patients with IPF were used to examine the effects and interactions of macrophage differentiation and hypoxia on fibrosis. We demonstrate that hypoxia-inducible factor 1-α (HIF1A) inhibition in late stages of bleomycin-induced injury attenuates pulmonary fibrosis in association, with reductions in ADORA2B expression in AAMs. Additionally, ADORA2B deletion or pharmacological antagonism along with HIF1A inhibition disrupts AAM differentiation and subsequent IL-6 production in cultured macrophages. These findings suggest that hypoxia, through HIF1A, contributes to the development and progression of pulmonary fibrosis through its regulation of ADORA2B expression on AAMs, cell differentiation, and production of profibrotic mediators. These studies support a potential role for HIF1A or ADORA2B antagonists in the treatment of IPF.-Philip, K., Mills, T. W., Davies, J., Chen, N.-Y., Karmouty-Quintana, H., Luo, F., Molina, J. G., Amione-Guerra, J., Sinha, N., Guha, A., Eltzschig, H. K., Blackburn, M. R. HIF1A up-regulates the ADORA2B receptor on alternatively activated macrophages and contributes to pulmonary fibrosis.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Macrófagos Alveolares , Macrófagos/metabolismo , Fibrose Pulmonar/metabolismo , Receptor A2B de Adenosina/biossíntese , Regulação para Cima , Adulto , Idoso , Animais , Bleomicina/efeitos adversos , Bleomicina/farmacologia , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/genética , Células Cultivadas , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Interleucina-6/biossíntese , Interleucina-6/genética , Macrófagos/patologia , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologia , Receptor A2B de Adenosina/genética
14.
J Rheumatol ; 44(6): 799-805, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28365584

RESUMO

OBJECTIVE: To examine the clinical correlates and survival in patients with antifibrillarin antibodies (AFA) in a large international study population consisting of well-characterized systemic sclerosis (SSc) cohorts from Canada, Australia, and the United States. METHODS: Baseline clinical data from the prospective cohorts (Canadian Scleroderma Research Group, the Australian Scleroderma Cohort Study, and the American Genetics versus Environment in Scleroderma Outcome Study) were investigated. Clinical variables were harmonized and sera were tested for AFA using a commercially available SSc profile line immunoassay, regardless of the immunofluorescence staining pattern. Association of demographic and clinical features with AFA was investigated by logistic or linear regression. Further, a survival analysis was performed by Cox regression analysis. RESULTS: A total of 1506 patients with SSc with complete serological profiles were included in the study. Fifty-two patients (3.5%) had antibodies detected against fibrillarin. Patients of African descent and Native North American ethnicity were more likely to be AFA-positive compared with other ethnicities. After adjustment for demographic factors, diffuse involvement, and intestinal bacterial overgrowth requiring antibiotics, gastrointestinal reflux disease showed a trend for association with AFA. Further, AFA positivity was associated with shorter survival independently of demographic factors and disease type (HR 1.76, 95% CI 1.11-2.79, p = 0.016). CONCLUSION: In this large multinational SSc cohort, AFA was associated with Native American ethnicity and was an independent predictor of mortality.


Assuntos
Autoanticorpos/sangue , Proteínas Cromossômicas não Histona/imunologia , Escleroderma Sistêmico/mortalidade , Adulto , Idoso , Autoanticorpos/imunologia , Feminino , Humanos , Índios Norte-Americanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/imunologia , Análise de Sobrevida , Taxa de Sobrevida
15.
FASEB J ; 30(2): 874-83, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26527068

RESUMO

Idiopathic pulmonary fibrosis is a devastating lung disease with limited treatment options. The signaling molecule adenosine is produced in response to injury and serves a protective role in early stages of injury and is detrimental during chronic stages of disease such as seen in lung conditions such as pulmonary fibrosis. Understanding the association of extracellular adenosine levels and the progression of pulmonary fibrosis is critical for designing adenosine based approaches to treat pulmonary fibrosis. The goal of this study was to use various models of experimental lung fibrosis to understand when adenosine levels are elevated during pulmonary fibrosis and whether these elevations were associated with disease progression and severity. To accomplish this, extracellular adenosine levels, defined as adenosine levels found in bronchioalveolar lavage fluid, were determined in mouse models of resolvable and progressive pulmonary fibrosis. We found that relative bronchioalveolar lavage fluid adenosine levels are progressively elevated in association with pulmonary fibrosis and that adenosine levels diminish in association with the resolution of lung fibrosis. In addition, treatment of these models with dipyridamole, an inhibitor of nucleoside transporters that potentiates extracellular adenosine levels, demonstrated that the resolution of lung fibrosis is blocked by the failure of adenosine levels to subside. Furthermore, exacerbating adenosine levels led to worse fibrosis in a progressive fibrosis model. Increased adenosine levels were associated with elevation of IL-6 and IL-17, which are important inflammatory cytokines in pulmonary fibrosis. These results demonstrate that extracellular adenosine levels are closely associated with the progression of experimental pulmonary fibrosis and that this signaling pathway may mediate fibrosis by regulating IL-6 and IL-17 production.


Assuntos
Adenosina/metabolismo , Fibrose Pulmonar Idiopática/metabolismo , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Proteínas de Transporte de Nucleosídeos/metabolismo , Animais , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Feminino , Fibrose Pulmonar Idiopática/patologia , Camundongos
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