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RATIONALE: Little is known about hospitalization in other types of interstitial lung disease (ILD) besides idiopathic pulmonary fibrosis (IPF). OBJECTIVES: We sought to determine the frequency of hospitalizations in various types of ILD and elucidate the association of hospitalization with outcomes. METHODS: An analysis of the Pulmonary Fibrosis Foundation Patient Registry data was performed. Inpatient hospitalization rates and survival following hospitalization were compared for various types of ILD. RESULTS: Hospitalization rates were similar across ILD types (40.6% of IPF participants, 42.8% of connective tissue disease related ILD (CTD-ILD), 44.9% of non-IPF idiopathic interstitial pneumonia (IIPs), 46.5% of chronic hypersensitivity pneumonitis (CHP) participants, and 53.3% of "other" ILD participants). All-cause hospitalization was not associated with decreased transplant-free survival (adjusted hazard ratio (AHR) 1.20, 95% CI: 0.98, 1.46, p=0.0759) after adjusting for co-morbidities and severity of illness; however respiratory-related hospitalization was (AHR 1.53, 95% CI: 1.23, 1.90, p=0.0001). CTD-ILD (HR 0.43, 95% CI: 0.25, 0.75, p=0.0031) and non-IPF IIP (HR 0.3, 95% CI: 0.15, 0.58, p=0.005) had a lower risk of death following hospitalization compared to IPF while CHP (HR 0.67, 95% CI: 0.37, 1.20, p=0.1747) and "other-ILD" (HR 0.54, 95% CI: 0.19, 1.54, p=0.25) had a comparable risk to IPF. CONCLUSION: Rates of hospitalization are similar across ILD subtypes. The risk of death or transplant following hospitalization is lower in CTD-ILD, CHP and non-IPF IIP compared to IPF participants. In a mixed population of ILD participants, all-cause hospitalizations were not associated with decreased transplant-free survival; however respiratory-related hospitalizations were.
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Background: Idiopathic pulmonary fibrosis (IPF) carries significant mortality and unpredictable progression, with limited therapeutic options. Designing trials with patient-meaningful endpoints, enhancing the reliability and interpretability of results, and streamlining the regulatory approval process are of critical importance to advancing clinical care in IPF. Methods: A landmark in-person symposium in June 2023 assembled 43 participants from the US and internationally, including patients with IPF, investigators, and regulatory representatives, to discuss the immediate future of IPF clinical trial endpoints. Patient advocates were central to discussions, which evaluated endpoints according to regulatory standards and the FDA's 'feels, functions, survives' criteria. Results: Three themes emerged: 1) consensus on endpoints mirroring the lived experiences of patients with IPF; 2) consideration of replacing forced vital capacity (FVC) as the primary endpoint, potentially by composite endpoints that include 'feels, functions, survives' measures or FVC as components; 3) support for simplified, user-friendly patient-reported outcomes (PROs) as either components of primary composite endpoints or key secondary endpoints, supplemented by functional tests as secondary endpoints and novel biomarkers as supportive measures (FDA Guidance for Industry (Multiple Endpoints in Clinical Trials) available at: https://www.fda.gov/media/162416/download). Conclusions: This report, detailing the proceedings of this pivotal symposium, suggests a potential turning point in designing future IPF clinical trials more attuned to outcomes meaningful to patients, and documents the collective agreement across multidisciplinary stakeholders on the importance of anchoring IPF trial endpoints on real patient experiences-namely, how they feel, function, and survive. There is considerable optimism that clinical care in IPF will progress through trials focused on patient-centric insights, ultimately guiding transformative treatment strategies to enhance patients' quality of life and survival.
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Fibrose Pulmonar Idiopática , Defesa do Paciente , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , National Institutes of Health (U.S.) , Qualidade de Vida , Reprodutibilidade dos Testes , Estados Unidos , Capacidade Vital , Ensaios Clínicos como AssuntoRESUMO
Despite progress in elucidation of disease mechanisms, identification of risk factors, biomarker discovery, and the approval of two medications to slow lung function decline in idiopathic pulmonary fibrosis and one medication to slow lung function decline in progressive pulmonary fibrosis, pulmonary fibrosis remains a disease with a high morbidity and mortality. In recognition of the need to catalyze ongoing advances and collaboration in the field of pulmonary fibrosis, the NHLBI, the Three Lakes Foundation, and the Pulmonary Fibrosis Foundation hosted the Pulmonary Fibrosis Stakeholder Summit on November 8-9, 2022. This workshop was held virtually and was organized into three topic areas: 1) novel models and research tools to better study pulmonary fibrosis and uncover new therapies, 2) early disease risk factors and methods to improve diagnosis, and 3) innovative approaches toward clinical trial design for pulmonary fibrosis. In this workshop report, we summarize the content of the presentations and discussions, enumerating research opportunities for advancing our understanding of the pathogenesis, treatment, and outcomes of pulmonary fibrosis.
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Pesquisa Biomédica , Fibrose Pulmonar Idiopática , Estados Unidos , Humanos , National Heart, Lung, and Blood Institute (U.S.) , Lagos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/terapia , Fatores de RiscoRESUMO
In idiopathic pulmonary fibrosis (IPF), the normal delicate lung architecture is replaced with rigid extracellular matrix (ECM) as a result of the accumulation of activated myofibroblasts and excessive deposition of ECM. Lamins have a role in fostering mechanosignaling from the ECM to the nucleus. Although there is a growing number of studies on lamins and associated diseases, there are no prior reports linking aberrations in lamins with pulmonary fibrosis. Here, we discovered, through analysis of RNA sequencing data, a novel isoform of lamin A/C that is more highly expressed in IPF compared with control lung. This novel LMNA (lamin A/C) splice variant includes retained introns 10 and 11 and exons 11 and 12 as documented by rapid amplification of cDNA ends. We found that this novel isoform is induced by stiff ECM. To better clarify the specific effects of this novel isoform of lamin A/C and how it may contribute to the pathogenesis of IPF, we transduced the lamin transcript into primary lung fibroblasts and alveolar epithelial cells and found that it impacts several biological effects, including cell proliferation, senescence, cell contraction, and the transition of fibroblasts to myofibroblasts. We also observed that type II epithelial cells and myofibroblasts in the IPF lung exhibited wrinkled nuclei, and this is notable because this has not been previously described and is consistent with laminopathy-mediated cellular effects.
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Fibrose Pulmonar Idiopática , Lamina Tipo A , Humanos , Lamina Tipo A/genética , Lamina Tipo A/metabolismo , Pulmão/patologia , Fibrose Pulmonar Idiopática/patologia , Fibroblastos/metabolismo , Miofibroblastos/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismoRESUMO
BACKGROUND: A genomic classifier for usual interstitial pneumonia (gUIP) has been shown to predict histological UIP with high specificity, increasing diagnostic confidence for idiopathic pulmonary fibrosis (IPF). Whether those with positive gUIP classification exhibit a progressive, IPF-like phenotype remains unknown. METHODS: A pooled, retrospective analysis of patients who underwent clinically indicated diagnostic bronchoscopy with gUIP testing at seven academic medical centres across the USA was performed. We assessed the association between gUIP classification and 18-month progression-free survival (PFS) using Cox proportional hazards regression. PFS was defined as the time from gUIP testing to death from any cause, lung transplant, ≥10% relative decline in forced vital capacity (FVC) or censoring at the time of last available FVC measure. Longitudinal change in FVC was then compared between gUIP classification groups using a joint regression model. RESULTS: Of 238 consecutive patients who underwent gUIP testing, 192 had available follow-up data and were included in the analysis, including 104 with positive gUIP classification and 88 with negative classification. In multivariable analysis, positive gUIP classification was associated with reduced PFS (hazard ratio 1.58, 95% CI 0.86-2.92; p=0.14), but this did not reach statistical significance. Mean annual change in FVC was -101.8â mL (95% CI -142.7- -60.9â mL; p<0.001) for those with positive gUIP classification and -73.2â mL (95% CI -115.2- -31.1â mL; p<0.001) for those with negative classification (difference 28.7â mL, 95% CI -83.2-25.9â mL; p=0.30). CONCLUSIONS: gUIP classification was not associated with differential rates of PFS or longitudinal FVC decline in a multicentre interstitial lung disease cohort undergoing bronchoscopy as part of the diagnostic evaluation.
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Fibrose Pulmonar Idiopática , Doenças Pulmonares Intersticiais , Humanos , Pulmão/patologia , Estudos Retrospectivos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/genética , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/genética , Capacidade Vital , Genômica , Progressão da DoençaRESUMO
Fibrosis involving the lung may occur in many settings, including in association with known environmental agents, connective tissue diseases, and exposure to drugs or radiation therapy. The most common form is referred to as 'idiopathic' since a causal agent or specific association has not been determined; the strongest risk factor for idiopathic pulmonary fibrosis is aging. Emerging studies indicate that targeting certain components of aging biology may be effective in mitigating age-associated fibrosis. While transforming growth factor-ß1 (TGF-ß1) is a central mediator of fibrosis in almost all contexts, and across multiple organs, it is not feasible to target this canonical pathway at the ligand-receptor level due to the pleiotropic nature of its actions; importantly, its homeostatic roles as a tumor-suppressor and immune-modulator make this an imprudent strategy. However, defining targets downstream of its receptor(s) that mediate fibrogenesis, while relatively dispenable for tumor- and immune-suppressive functions may aid in developing safer and more effective therapies. In this review, we explore molecular targets that, although TGF-ß1 induced/activated, may be relatively more selective in mediating tissue fibrosis. Additionally, we explore epigenetic mechanisms with global effects on the fibrogenic process, as well as metabolic pathways that regulate aging and fibrosis.
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Fibrose Pulmonar Idiopática , Fator de Crescimento Transformador beta1 , Fibroblastos/metabolismo , Fibrose , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease with a variable clinical course. Biomarkers that predict patient outcomes are needed. We leveraged data from 300 patients in the multicenter IPF-PRO Registry to determine associations between circulating proteins and the composite outcome of respiratory death or lung transplant. Plasma collected at enrollment was analyzed using aptamer-based proteomics (1305 proteins). Over a median follow-up of 30.4 months, there were 76 respiratory deaths and 26 lung transplants. In unadjusted univariable analyses, 61 proteins were significantly associated with the outcome (hazard ratio > 2 or < 0.5, corrected p ≤ 0.05). In multivariable analyses, a set of 4 clinical measures and 47 unique proteins predicted the probability of respiratory death or lung transplant with an optimism-corrected C-index of 0.76. Our results suggest that select circulating proteins strongly associate with the risk of mortality in patients with IPF and confer information independent of clinical measures.
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Fibrose Pulmonar Idiopática , Transplante de Pulmão , Estudos de Coortes , Humanos , Proteômica , Sistema de RegistrosRESUMO
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with few treatment options. N-acetylcysteine (NAC) is a well-tolerated, inexpensive treatment with antioxidant and anti-fibrotic properties. The National Heart, Lung, and Blood Institute (NHLBI)-sponsored PANTHER (Prednisone Azathioprine and NAC therapy in IPF) trial confirmed the harmful effects of immunosuppression in IPF, and did not show a benefit to treatment with NAC. However, a post hoc analysis revealed a potential beneficial effect of NAC in a subgroup of individuals carrying a specific genetic variant, TOLLIP rs3750920 TT genotype, present in about 25% of patients with IPF. Here, we present the design and rationale for the Phase III, multi-center, randomized, double-blind, placebo-controlled Prospective Treatment Efficacy in IPF Using Genotype for NAC Selection (PRECISIONS) clinical trial. METHODS: The PRECISIONS trial will randomize 200 patients with IPF and the TOLLIP rs3750920 TT genotype 1:1 to oral N-acetylcysteine (600 mg tablets taken three times a day) or placebo for a 24-month duration. The primary endpoint is the composite of time to 10% relative decline in forced vital capacity (FVC), first respiratory hospitalization, lung transplantation, or death from any cause. Secondary endpoints include change in patient-reported outcome scores and proportion of participants with treatment-emergent adverse events. Biospecimens, including blood, buccal, and fecal will be collected longitudinally for future research purposes. Study participants will be offered enrollment in a home spirometry substudy, which explores time to 10% relative FVC decline measured at home, and its comparison with study visit FVC. DISCUSSION: The sentinel observation of a potential pharmacogenetic interaction between NAC and TOLLIP polymorphism highlights the urgent, unmet need for better, molecularly focused, and precise therapeutic strategies in IPF. The PRECISIONS clinical trial is the first study to use molecularly-focused techniques to identify patients with IPF most likely to benefit from treatment. PRECISIONS has the potential to shift the paradigm in how trials in this condition are designed and executed, and is the first step toward personalized medicine for patients with IPF. Trial Registration ClinicalTrials.gov identifier: NCT04300920. Registered March 9, 2020. https://clinicaltrials.gov/ct2/show/NCT04300920.
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Acetilcisteína , Fibrose Pulmonar Idiopática , Humanos , Acetilcisteína/uso terapêutico , Método Duplo-Cego , Genótipo , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/genética , Resultado do Tratamento , Capacidade Vital , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como Assunto , Ensaios Clínicos Fase III como AssuntoRESUMO
BACKGROUND: Oxidative stress contributes to the complex pathophysiology of sickle cell disease. Oral therapy with pharmaceutical-grade l-glutamine (USAN, glutamine) has been shown to increase the proportion of the reduced form of nicotinamide adenine dinucleotides in sickle cell erythrocytes, which probably reduces oxidative stress and could result in fewer episodes of sickle cell-related pain. METHODS: In a multicenter, randomized, placebo-controlled, double-blind, phase 3 trial, we tested the efficacy of pharmaceutical-grade l-glutamine (0.3 g per kilogram of body weight per dose) administered twice daily by mouth, as compared with placebo, in reducing the incidence of pain crises among patients with sickle cell anemia or sickle ß0-thalassemia and a history of two or more pain crises during the previous year. Patients who were receiving hydroxyurea at a dose that had been stable for at least 3 months before screening continued that therapy through the 48-week treatment period. RESULTS: A total of 230 patients (age range, 5 to 58 years; 53.9% female) were randomly assigned, in a 2:1 ratio, to receive l-glutamine (152 patients) or placebo (78 patients). The patients in the l-glutamine group had significantly fewer pain crises than those in the placebo group (P=0.005), with a median of 3.0 in the l-glutamine group and 4.0 in the placebo group. Fewer hospitalizations occurred in the l-glutamine group than in the placebo group (P=0.005), with a median of 2.0 in the l-glutamine group and 3.0 in the placebo group. Two thirds of the patients in both trial groups received concomitant hydroxyurea. Low-grade nausea, noncardiac chest pain, fatigue, and musculoskeletal pain occurred more frequently in the l-glutamine group than in the placebo group. CONCLUSIONS: Among children and adults with sickle cell anemia, the median number of pain crises over 48 weeks was lower among those who received oral therapy with l-glutamine, administered alone or with hydroxyurea, than among those who received placebo, with or without hydroxyurea. (Funded by Emmaus Medical; ClinicalTrials.gov number, NCT01179217 .).
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Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/uso terapêutico , Glutamina/uso terapêutico , Hidroxiureia/uso terapêutico , Manejo da Dor , Administração Oral , Adolescente , Adulto , Anemia Falciforme/complicações , Criança , Pré-Escolar , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Glutamina/efeitos adversos , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Dor/prevenção & controle , Adulto Jovem , Talassemia beta/tratamento farmacológicoRESUMO
Importance: Although effective agents are available to prevent painful vaso-occlusive episodes of sickle cell disease (SCD), there are no disease-modifying therapies for ongoing painful vaso-occlusive episodes; treatment remains supportive. A previous phase 3 trial of poloxamer 188 reported shortened duration of painful vaso-occlusive episodes in SCD, particularly in children and participants treated with hydroxyurea. Objective: To reassess the efficacy of poloxamer 188 for vaso-occlusive episodes. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled, multicenter, international trial conducted from May 2013 to February 2016 that included 66 hospitals in 12 countries and 60 cities; 388 individuals with SCD (hemoglobin SS, SC, S-ß0 thalassemia, or S-ß+ thalassemia disease) aged 4 to 65 years with acute moderate to severe pain typical of painful vaso-occlusive episodes requiring hospitalization were included. Interventions: A 1-hour 100-mg/kg loading dose of poloxamer 188 intravenously followed by a 12-hour to 48-hour 30-mg/kg/h continuous infusion (n = 194) or placebo (n = 194). Main Outcomes and Measures: Time in hours from randomization to the last dose of parenteral opioids among all participants and among those younger than 16 years as a separate subgroup. Results: Of 437 participants assessed for eligibility, 388 were randomized (mean age, 15.2 years; 176 [45.4%] female), the primary outcome was available for 384 (99.0%), 15-day follow-up contacts were available for 357 (92.0%), and 30-day follow-up contacts were available for 368 (94.8%). There was no significant difference between the groups for the mean time to last dose of parenteral opioids (81.8 h for the poloxamer 188 group vs 77.8 h for the placebo group; difference, 4.0 h [95% CI, -7.8 to 15.7]; geometric mean ratio, 1.2 [95% CI, 1.0-1.5]; P = .09). Based on a significant interaction of age and treatment (P = .01), there was a treatment difference in time from randomization to last administration of parenteral opioids for participants younger than 16 years (88.7 h in the poloxamer 188 group vs 71.9 h in the placebo group; difference, 16.8 h [95% CI, 1.7-32.0]; geometric mean ratio, 1.4 [95% CI, 1.1-1.8]; P = .008). Adverse events that were more common in the poloxamer 188 group than the placebo group included hyperbilirubinemia (12.7% vs 5.2%); those more common in the placebo group included hypoxia (12.0% vs 5.3%). Conclusions and Relevance: Among children and adults with SCD, poloxamer 188 did not significantly shorten time to last dose of parenteral opioids during vaso-occlusive episodes. These findings do not support the use of poloxamer 188 for vaso-occlusive episodes. Trial Registration: ClinicalTrials.gov Identifier: NCT01737814.
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Anemia Falciforme/tratamento farmacológico , Dor/tratamento farmacológico , Poloxâmero/uso terapêutico , Vasodilatadores/uso terapêutico , Adolescente , Adulto , Analgésicos Opioides/uso terapêutico , Anemia Falciforme/complicações , Criança , Método Duplo-Cego , Feminino , Humanos , Masculino , Dor/etiologia , Placebos/efeitos adversos , Placebos/uso terapêutico , Poloxâmero/efeitos adversos , Vasodilatadores/efeitos adversos , Adulto JovemRESUMO
Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder, characterized by the pathologic clonal proliferation and accumulation of immature Langerhans cells within organs. Multiple organ systems can be affected, resulting in a spectrum of clinical manifestations. Isolated gastrointestinal involvement in LCH is rare and usually presents in childhood as a multisystem disease and usually has poor outcomes. We describe a 20-year-old Hispanic female with multifocal, single-system gastrointestinal LCH. Initially diagnosed from a CD1a, S100, and CD207 (Langerin) positive appendix tissue after an appendectomy and confirmed multifocal with an endoscopy. She had a full clinical and endoscopic resolution of disease with cytarabine therapy.
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Gastroenteropatias/patologia , Histiocitose de Células de Langerhans/patologia , Adulto , Antimetabólitos Antineoplásicos/uso terapêutico , Citarabina/uso terapêutico , Feminino , Gastroenteropatias/complicações , Gastroenteropatias/tratamento farmacológico , Histiocitose de Células de Langerhans/complicações , Histiocitose de Células de Langerhans/tratamento farmacológico , Humanos , Prognóstico , Adulto JovemRESUMO
The Ewing sarcoma family of tumors (ESFT) are high-grade small round blue cell malignancies traditionally presenting in children and adolescents. The most common site of primary disease is bone, though extraskeletal primary sites are well-recognized. We present 6 cases of primary ESFT of the kidney and 1 case of the adrenal gland. Patients were 11 to 18 years of age at diagnosis. Metastases at diagnosis were present in most cases (n=6). All patients underwent surgery, and most received radiation (n=5). Five patients relapsed after initial remission. Comprehensive review of the primary renal ESFT literature was used to analyze various factors, including age, sex, disease metrics, metastases at diagnoses, and overall survival in a total of 362 cases. Notably, while the general ESFT population has reported rates of metastasis at diagnosis of 20% to 25%, this rate in the renal ESFT population was 53% with a rate of 59% in adolescent and young-adult patients (11 to 24 y). Nodal disease at diagnosis was present in 24% of renal ESFT cases compared with 3.2% in patients with primary skeletal ESFT. While this malignant process may share histologic and molecular features with its bone and soft tissue counterparts, primary renal ESFT presentations seem to be more aggressive and have worse outcomes.
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Neoplasias Renais/patologia , Sarcoma de Ewing/patologia , Adolescente , Criança , Feminino , Humanos , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , Neoplasias Renais/terapia , Masculino , Sarcoma de Ewing/genética , Sarcoma de Ewing/mortalidade , Sarcoma de Ewing/terapiaRESUMO
BACKGROUND: Numerous publications suggest an association between herpes virus infection and idiopathic pulmonary fibrosis (IPF). These reports have employed immunohistochemistry, in situ hybridization and/or PCR, which are susceptible to specificity artifacts. METHODS: We investigated the possible association between IPF and viral RNA expression using next-generation sequencing, which has the potential to provide a high degree of both sensitivity and specificity. We quantified viral RNA expression for 740 viruses in 28 IPF patient lung biopsy samples and 20 controls. Key RNA-seq results were confirmed using Real-time RT-PCR for select viruses (EBV, HCV, herpesvirus saimiri and HERV-K). RESULTS: We identified sporadic low-level evidence of viral infections in our lung tissue specimens, but did not find a statistical difference for expression of any virus, including EBV, herpesvirus saimiri and HERV-K, between IPF and control lungs. CONCLUSIONS: To the best of our knowledge, this is the first publication that employs RNA-seq to assess whether viral infections are linked to the pathogenesis of IPF. Our results do not address the role of viral infection in acute exacerbations of IPF, however, this analysis patently did not support an association between herpes virus detection and IPF.
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Fibrose Pulmonar Idiopática/virologia , Pulmão/virologia , RNA Viral/análise , RNA-Seq , Viroses/complicações , Estudos de Casos e Controles , Humanos , Fibrose Pulmonar Idiopática/patologia , Pulmão/patologia , Reação em Cadeia da Polimerase em Tempo RealRESUMO
BACKGROUND: Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) play important roles in the turnover of extracellular matrix and in the pathogenesis of idiopathic pulmonary fibrosis (IPF). This study aimed to determine the utility of circulating MMPs and TIMPs in distinguishing patients with IPF from controls and to explore associations between MMPs/TIMPs and measures of disease severity in patients with IPF. METHODS: The IPF cohort (n = 300) came from the IPF-PRO Registry, an observational multicenter registry of patients with IPF that was diagnosed or confirmed at the enrolling center in the past 6 months. Controls (n = 100) without known lung disease came from a population-based registry. Generalized linear models were used to compare circulating concentrations of MMPs 1, 2, 3, 7, 8, 9, 12, and 13 and TIMPs 1, 2, and 4 between patients with IPF and controls, and to investigate associations between circulating levels of these proteins and measures of IPF severity. Multivariable models were fit to identify the MMP/TIMPs that best distinguished patients with IPF from controls. RESULTS: All the MMP/TIMPs analyzed were present at significantly higher levels in patients with IPF compared with controls except for TIMP2. Multivariable analyses selected MMP8, MMP9 and TIMP1 as top candidates for distinguishing patients with IPF from controls. Higher concentrations of MMP7, MMP12, MMP13 and TIMP4 were significantly associated with lower diffusion capacity of the lung for carbon monoxide (DLCO) % predicted and higher composite physiologic index (worse disease). MMP9 was associated with the composite physiologic index. No MMP/TIMPs were associated with forced vital capacity % predicted. CONCLUSIONS: Circulating MMPs and TIMPs were broadly elevated among patients with IPF. Select MMP/TIMPs strongly associated with measures of disease severity. Our results identify potential MMP/TIMP targets for further development as disease-related biomarkers.
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Fibrose Pulmonar Idiopática/sangue , Metaloproteinases da Matriz Secretadas/sangue , Inibidores Teciduais de Metaloproteinases/sangue , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Fibrose Pulmonar Idiopática/patologia , Modelos Lineares , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Capacidade VitalRESUMO
Endogenous IL-15 deficiency promotes lung fibrosis; therefore, we examined the effect of induced IL-15 in restricting the progression of lung fibrosis. Our objective in this work was to establish a novel therapeutic molecule for pulmonary fibrosis. Western blot, qPCR, and ELISA were performed on the lung tissues of IL-15-deficient mice, and recombinant IL-15 (rIL-15)-treated CC10-IL-13 and CC10-TGF-α mice, and allergen-challenged CC10-IL-15 mice were examined to establish the antifibrotic effect of IL-15 in lung fibrosis. We show that endogenous IL-15 deficiency induces baseline profibrotic cytokine and collagen accumulation in the lung, and pharmacological delivery of rIL-15 downregulates Aspergillus antigen-induced lung collagen, the profibrotic cytokines IL-13 and TGF-ß1, and α-SMA+ and FSP1+ cells in mice. To confirm that overexpression of IL-15 diminishes pulmonary fibrosis, we generated CC10-rtTA-tetO7-IL-15 transgenic mice and challenged them with Aspergillus antigen. Aspergillus antigen-challenged, doxycycline (DOX)-treated CC10-IL-15 transgenic mice exhibited decreased collagen accumulation, profibrotic cytokine (IL-13 and TGF-ß1) expression, and α-SMA+ and FSP1+ cells compared with IL-15-overexpressing mice not treated with DOX. Additionally, to establish that the antifibrotic effect of IL-15 is not limited to allergen-induced fibrosis, we showed that rIL-15 or IL-15 agonist treatment restricted pulmonary fibrosis even in CC10-IL-13 and CC10-TGF-α mice. Mechanistically, we show that T-helper cell type 17 suppressor IL-15-responsive RORγ+ T regulatory cells are induced in DOX-treated, allergen-challenged IL-15-overexpressing mice, which may be a novel pathway for restricting progression of pulmonary fibrosis. Taken together, our data establishes antifibrotic activity of IL-15 that might be a novel therapeutic molecule to combat the development of pulmonary fibrosis.
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Alérgenos/efeitos adversos , Interleucina-13/efeitos adversos , Interleucina-15/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Fator de Crescimento Transformador alfa/efeitos adversos , Remodelação das Vias Aéreas , Animais , Aspergillus fumigatus , Brônquios/patologia , Colágeno/metabolismo , Doxiciclina/farmacologia , Doxiciclina/uso terapêutico , Interleucina-15/deficiência , Pulmão/metabolismo , Pulmão/patologia , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Proteínas/farmacologia , Proteínas/uso terapêutico , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Fibrose Pulmonar/fisiopatologia , Proteínas Recombinantes de Fusão , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismoRESUMO
Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative lung disease, and fibroblast-myofibroblast differentiation (FMD) is thought to be a key event in the pathogenesis of IPF. Histone deacetylase-8 (HDAC8) has been shown to associate with α-smooth muscle actin (α-SMA; a marker of FMD) and regulates cell contractility in vascular smooth muscle cells. However, the role of HDAC8 in FMD or pulmonary fibrosis has never been reported. This study investigated the role of HDAC8 in pulmonary fibrosis with a focus on FMD. We observed that HDAC8 expression was increased in IPF lung tissue as well as transforming growth factor (TGF)ß1-treated normal human lung fibroblasts (NHLFs). Immunoprecipitation experiments revealed that HDAC8 was associated with α-SMA in TGFß1-treated NHLFs. HDAC8 inhibition with NCC170 (HDAC8-selective inhibitor) repressed TGFß1-induced fibroblast contraction and α-SMA protein expression in NHLFs cultured in collagen gels. HDAC8 inhibition with HDAC8 siRNA also repressed TGFß1-induced expression of profibrotic molecules such as fibronectin and increased expression of antifibrotic molecules such as peroxisome proliferator-activated receptor-γ (PPARγ). Chromatin immunoprecipitation quantitative PCR using an antibody against H3K27ac (histone H3 acetylated at lysine 27; a known HDAC8 substrate and a marker for active enhancers) suggested that HDAC8 inhibition with NCC170 ameliorated TGFß1-induced loss of H3K27ac at the PPARγ gene enhancer. Furthermore, NCC170 treatment significantly decreased fibrosis measured by Ashcroft score as well as expression of type 1 collagen and fibronectin in bleomycin-treated mouse lungs. These data suggest that HDAC8 contributes to pulmonary fibrosis and that there is a therapeutic potential for HDAC8 inhibitors to treat IPF as well as other fibrotic lung diseases.
Assuntos
Inibidores de Histona Desacetilases/farmacologia , Fibrose Pulmonar Idiopática/tratamento farmacológico , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Miofibroblastos/enzimologia , Proteínas Repressoras/antagonistas & inibidores , Acetilação/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Histona Desacetilases/biossíntese , Histonas/metabolismo , Humanos , Fibrose Pulmonar Idiopática/enzimologia , Fibrose Pulmonar Idiopática/patologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Miofibroblastos/patologia , PPAR gama/metabolismo , Proteínas Repressoras/biossíntese , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Subfertility is a major concern of long-term cancer survivors at the reproductive age. We have previously demonstrated that a potent humanin analogue, HNG, protected chemotherapy-induced apoptosis in germ cells but not cancer cells in a metastatic melanoma allograft model. In this study, we utilized severe combined immuno-deficiency (SCID) mice bearing human medulloblastoma to study the effect of HNG in Temozolomide (TMZ) induced male germ cell apoptosis and white blood cell (WBC) suppression. Human medulloblastoma DAOY cells were injected subcutaneously into the right flank of male SCID mice. Three weeks later, groups of tumor-bearing mice received one of the following treatments: vehicle, HNG, TMZ, or TMZâ¯+â¯HNG. 24â¯h after last injection, the tumors weights, complete blood counts, liver and spleen weights, male germ cell apoptosis was assessed. HNG did not affect TMZ's significant anti-tumor action. HNG significantly prevented TMZ-induced germ cell apoptosis and attenuated the suppressed total WBC and granulocyte counts in SCID mice with or without TMZ treatment. HNG also attenuated TMZ-induced body weight loss and decrease of spleen and liver weights. In conclusion, HNG ameliorated TMZ-induced germ cell apoptosis; WBC and granulocytes loss; and decreased body/organ weights without compromising the TMZ's anti-cancer action on medulloblastoma xenografts in SCID mice.
Assuntos
Apoptose/efeitos dos fármacos , Neoplasias Cerebelares/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Meduloblastoma/tratamento farmacológico , Espermatozoides/efeitos dos fármacos , Temozolomida/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Antineoplásicos Alquilantes/farmacologia , Linhagem Celular Tumoral , Neoplasias Cerebelares/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Meduloblastoma/patologia , Camundongos SCID , Tamanho do Órgão/efeitos dos fármacos , Espermatozoides/citologia , Baço/efeitos dos fármacos , Baço/patologia , Carga Tumoral/efeitos dos fármacosRESUMO
BACKGROUND: Airway obstruction is a physiologic feature of asthma, and IL-15 might have an important role in asthma pathogenesis. OBJECTIVE: We tested the hypothesis that regulation of IL-15 is critical for preservation of allergen-induced airway hyperresponsiveness (AHR), airway resistance, and compliance in response to methacholine. METHODS: Airway inflammation, AHR, resistance, and compliance were assessed in Il15 gene-deficient mice and IL-15-overexpressing mice in an allergen-induced murine model of asthma. We assessed eosinophil numbers by using anti-major basic protein immunostaining, goblet cell hyperplasia by using periodic acid-Schiff staining, and cytokine and chemokine levels by performing quantitative PCR and ELISA. RESULTS: We made a novel observation that IL-15 deficiency promotes baseline airway resistance in naive mice. Moreover, rIL-15 delivery to the lung downregulates expression of proinflammatory cytokines and improves allergen-induced AHR, airway resistance, and compliance. These observations were further validated in doxycycline-inducible CC10-IL-15 bitransgenic mice. Doxycycline-exposed, Aspergillus species extract-challenged CC10-IL-15 bitransgenic mice exhibited significantly reduced levels of proinflammatory cytokines (IL-4, IL-5, and IL-13) and decreased goblet cell hyperplasia. Airway obstruction, including AHR and airway resistance, was diminished in allergen-challenged doxycycline-exposed compared with non-doxycycline-exposed CC10-IL-15 bitransgenic mice. Mechanistically, we observed that IL-15-mediated protection of airway obstruction is associated with induced IFN-γ- and IL-10-producing regulatory CD4+CD25+ forkhead box p3 (Foxp3)+ T cells. Additionally, we found that a human IL-15 agonist (ALT-803) improved airway resistance and compliance in an experimental asthma model. CONCLUSION: We report our novel finding that IL-15 has a potent inhibitory effect on the airway obstruction that occurs in response to environmental allergens.