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1.
Am J Respir Crit Care Med ; 210(4): 435-443, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-38484130

RESUMO

Rationale: Idiopathic pulmonary fibrosis is a fatal and progressive disease with limited treatment options. Objectives: We sought to assess the efficacy and safety of CC-90001, an oral inhibitor of c-Jun N-terminal kinase 1, in patients with idiopathic pulmonary fibrosis. Methods: In a Phase 2, randomized (1:1:1), double-blind, placebo-controlled study (ClinicalTrials.gov ID: NCT03142191), patients received CC-90001 (200 or 400 mg) or placebo once daily for 24 weeks. Background antifibrotic treatment (pirfenidone) was allowed. The primary endpoint was change in the percentage of predicted FVC (ppFVC) from baseline to Week 24; secondary endpoints included safety. Measurements and Main Results: In total, 112 patients received at least one dose of study drug. The study was terminated early because of a strategic decision made by the sponsor. Ninety-one patients (81%) completed the study. The least-squares mean changes from baseline in ppFVC at Week 24 were -3.1% (placebo), -2.1% (200 mg), and -1.0% (400 mg); the differences compared with placebo were 1.1% (200 mg; 95% confidence interval: -2.1, 4.3; P = 0.50) and 2.2% (400 mg; 95% confidence interval: -1.1, 5.4; P = 0.19). Adverse event frequency was similar in patients in the combined CC-90001 arms versus placebo. The most common adverse events were nausea, diarrhea, and vomiting, which were more frequent in patients in CC-90001 arms versus placebo. Fewer patients in the CC-90001 arms than in the placebo arm experienced cough and dyspnea. Conclusions: Treatment with CC-90001 over 24 weeks led to numerical improvements in ppFVC in patients with idiopathic pulmonary fibrosis compared with placebo. CC-90001 was generally well tolerated, which was consistent with previous studies. Clinical trial registered with www.clinicaltrials.gov (NCT03142191).


Assuntos
Fibrose Pulmonar Idiopática , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/fisiopatologia , Método Duplo-Cego , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Resultado do Tratamento , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Adulto
2.
Am J Respir Cell Mol Biol ; 71(2): 229-241, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38635761

RESUMO

Aging poses a global public health challenge, which is linked to the rise of age-related lung diseases. The precise understanding of the molecular and genetic changes in the aging lung that elevate the risk of acute and chronic lung diseases remains incomplete. Alveolar type II (AT2) cells are stem cells that maintain epithelial homeostasis and repair the lung after injury. AT2 progenitor function decreases with aging. The maintenance of AT2 function requires niche support from other cell types, but little has been done to characterize alveolar alterations with aging in the AT2 niche. To systematically profile the genetic changes associated with age, we present a single-cell transcriptional atlas comprising nearly half a million cells from the healthy lungs of human subjects spanning various ages, sexes, and smoking statuses. Most annotated cell lineages in aged lungs exhibit dysregulated genetic programs. Specifically, the aged AT2 cells demonstrate loss of epithelial identities, heightened inflammaging characterized by increased expression of AP-1 (Activator Protein-1) transcription factor and chemokine genes, and significantly increased cellular senescence. Furthermore, the aged mesenchymal cells display a remarkable decrease in collagen and elastin transcription and a loss of support to epithelial cell stemness. The decline of the AT2 niche is further exacerbated by a dysregulated genetic program in macrophages and dysregulated communications between AT2 and macrophages in aged human lungs. These findings highlight the dysregulations observed in both AT2 stem cells and their supportive niche cells, potentially contributing to the increased susceptibility of aged populations to lung diseases.


Assuntos
Envelhecimento , Células Epiteliais Alveolares , Pulmão , Nicho de Células-Tronco , Transcriptoma , Humanos , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Envelhecimento/genética , Pulmão/metabolismo , Pulmão/patologia , Transcriptoma/genética , Idoso , Pessoa de Meia-Idade , Masculino , Senescência Celular/genética , Perfilação da Expressão Gênica , Feminino , Adulto , Células-Tronco/metabolismo
3.
Am J Respir Cell Mol Biol ; 71(2): 242-253, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38657143

RESUMO

Idiopathic pulmonary fibrosis (IPF) is an aging-associated interstitial lung disease resulting from repeated epithelial injury and inadequate epithelial repair. Alveolar type II cells (AEC2s) are progenitor cells that maintain epithelial homeostasis and repair the lung after injury. In the current study, we assessed lipid metabolism in AEC2s from human lungs of patients with IPF and healthy donors, as well as AEC2s from bleomycin-injured young and old mice. Through single-cell RNA sequencing, we observed that lipid metabolism-related genes were downregulated in IPF AEC2s and bleomycin-injured mouse AEC2s. Aging aggravated this decrease and hindered recovery of lipid metabolism gene expression in AEC2s after bleomycin injury. Pathway analyses revealed downregulation of genes related to lipid biosynthesis and fatty acid ß-oxidation in AEC2s from IPF lungs and bleomycin-injured, old mouse lungs compared with the respective controls. We confirmed decreased cellular lipid content in AEC2s from IPF lungs and bleomycin-injured, old mouse lungs using immunofluorescence staining and flow cytometry. Futhermore, we show that lipid metabolism was associated with AEC2 progenitor function. Lipid supplementation and PPARγ (peroxisome proliferator activated receptor γ) activation promoted progenitor renewal capacity of both human and mouse AEC2s in three-dimensional organoid cultures. Lipid supplementation also increased AEC2 proliferation and expression of SFTPC in AEC2s. In summary, we identified a lipid metabolism deficiency in AEC2s from lungs of patients with IPF and bleomycin-injured old mice. Restoration of lipid metabolism homeostasis in AEC2s might promote AEC2 progenitor function and offer new opportunities for therapeutic approaches to IPF.


Assuntos
Envelhecimento , Células Epiteliais Alveolares , Bleomicina , Fibrose Pulmonar Idiopática , Metabolismo dos Lipídeos , Células-Tronco , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Animais , Humanos , Camundongos , Células-Tronco/metabolismo , Células-Tronco/patologia , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Envelhecimento/metabolismo , Envelhecimento/patologia , PPAR gama/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Feminino
4.
Am J Physiol Lung Cell Mol Physiol ; 327(2): L160-L172, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38771132

RESUMO

The alveolar type II epithelial cells (AEC2s) act as stem cells in the lung for alveolar epithelial maintenance and repair. Chemokine C-X-C motif chemokine 10 (CXCL10) is expressed in injured tissues, modulating multiple cellular functions. AEC2s, previously reported to release chemokines to recruit leukocytes, were found in our study to secrete CXCL10 after bleomycin injury. We found that Sftpc-Cxcl10 transgenic mice were protected from bleomycin injury. The transgenic mice showed an increase in the AEC2 population in the lung by flow cytometry analysis. Both endogenous and exogenous CXCL10 promoted the colony formation efficiency of AEC2s in a three-dimensional (3-D) organoid growth assay. We identified that the regenerative effect of CXCL10 was CXCR3 independent using Cxcr3-deficient mice, but it was related to the TrkA pathway. Binding experiments showed that CXCL10 interacted with TrkA directly and reversibly. This study demonstrates a previously unidentified AEC2 autocrine signaling of CXCL10 to promote their regeneration and proliferation, probably involving a CXCR3-independent TrkA pathway.NEW & NOTEWORTHY CXCL10 may aid in lung injury recovery by promoting the proliferation of alveolar stem cells and using a distinct regulatory pathway from the classical one.


Assuntos
Células Epiteliais Alveolares , Quimiocina CXCL10 , Receptores CXCR3 , Animais , Camundongos , Células Epiteliais Alveolares/metabolismo , Proliferação de Células , Quimiocina CXCL10/metabolismo , Quimiocina CXCL10/genética , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/patologia , Receptores CXCR3/metabolismo , Receptores CXCR3/genética , Regeneração , Transdução de Sinais
5.
Am J Respir Cell Mol Biol ; 69(1): 45-56, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36927333

RESUMO

Progressive pulmonary fibrosis results from a dysfunctional tissue repair response and is characterized by fibroblast proliferation, activation, and invasion and extracellular matrix accumulation. Lung fibroblast heterogeneity is well recognized. With single-cell RNA sequencing, fibroblast subtypes have been reported by recent studies. However, the roles of fibroblast subtypes in effector functions in lung fibrosis are not well understood. In this study, we incorporated the recently published single-cell RNA-sequencing datasets on murine lung samples of fibrosis models and human lung samples of fibrotic diseases and analyzed fibroblast gene signatures. We identified and confirmed the novel fibroblast subtypes we reported recently across all samples of both mouse models and human lung fibrotic diseases, including idiopathic pulmonary fibrosis, systemic sclerosis-associated interstitial lung disease, and coronavirus disease (COVID-19). Furthermore, we identified specific cell surface proteins for each fibroblast subtype through differential gene expression analysis, which enabled us to isolate primary cells representing distinct fibroblast subtypes by flow cytometry sorting. We compared matrix production, including fibronectin, collagen, and hyaluronan, after profibrotic factor stimulation and assessed the invasive capacity of each fibroblast subtype. Our results suggest that in addition to myofibroblasts, lipofibroblasts and Ebf1+ (Ebf transcription factor 1+) fibroblasts are two important fibroblast subtypes that contribute to matrix deposition and also have enhanced invasive, proliferative, and contraction phenotypes. The histological locations of fibroblast subtypes are identified in healthy and fibrotic lungs by these cell surface proteins. This study provides new insights to inform approaches to targeting lung fibroblast subtypes to promote the development of therapeutics for lung fibrosis.


Assuntos
COVID-19 , Fibrose Pulmonar Idiopática , Humanos , Camundongos , Animais , COVID-19/metabolismo , Fibroblastos/metabolismo , Pulmão/patologia , Fibrose Pulmonar Idiopática/patologia , Fibrose , Proteínas de Membrana/metabolismo
6.
Am J Respir Cell Mol Biol ; 68(3): 302-313, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36318668

RESUMO

Loss of epithelial integrity, bronchiolarization, and fibroblast activation are key characteristics of idiopathic pulmonary fibrosis (IPF). Prolonged accumulation of basal-like cells in IPF may impact the fibrotic niche to promote fibrogenesis. To investigate their role in IPF, basal cells were isolated from IPF explant and healthy donor lung tissues. Single-cell RNA sequencing was used to assess differentially expressed genes in basal cells. Basal cell and niche interaction was demonstrated with the sLP-mCherry niche labeling system. Luminex assays were used to assess cytokines secreted by basal cells. The role of basal cells in fibroblast activation was studied. Three-dimensional organoid culture assays were used to interrogate basal cell effects on AEC2 (type 2 alveolar epithelial cell) renewal capacity. Perturbation was used to investigate WNT7A function in vitro and in a repetitive bleomycin model in vivo. We found that WNT7A is highly and specifically expressed in basal-like cells. Proteins secreted by basal cells can be captured by neighboring fibroblasts and AEC2s. Basal cells or basal cell-conditioned media activate fibroblasts through WNT7A. Basal cell-derived WNT7A inhibits AEC2 progenitor cell renewal in three-dimensional organoid cultures. Neutralizing antibodies against WNT7A or a small molecule inhibitor of Frizzled signaling abolished basal cell-induced fibroblast activation and attenuated lung fibrosis in mice. In summary, basal cells and basal cell-derived WNT7A are key components of the fibrotic niche, providing a unique non-stem cell function of basal cells in IPF progression and a novel targeting strategy for IPF.


Assuntos
Fibrose Pulmonar Idiopática , Animais , Camundongos , Bleomicina/farmacologia , Fibroblastos/metabolismo , Fibrose , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/patologia , Transdução de Sinais
7.
Am J Physiol Cell Physiol ; 325(2): C483-C495, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37458437

RESUMO

Pulmonary fibrosis comprises a range of chronic interstitial lung diseases (ILDs) that impose a significant burden on patients and public health. Among these, idiopathic pulmonary fibrosis (IPF), a disease of aging, is the most common and most severe form of ILD and is treated largely by lung transplantation. The lack of effective treatments to stop or reverse lung fibrosis-in fact, fibrosis in most organs-has sparked the need to understand causative mechanisms with the goal of identifying critical points for potential therapeutic intervention. Findings from many groups have indicated that repeated injury to the alveolar epithelium-where gas exchange occurs-leads to stem cell exhaustion and impaired alveolar repair that, in turn, triggers the onset and progression of fibrosis. Cellular senescence of alveolar epithelial progenitors is a critical cause of stemness failure. Hence, senescence impairs repair and thus contributes significantly to fibrosis. In this review, we discuss recent evidence indicating that senescence of epithelial progenitor cells impairs alveolar homeostasis and repair creating a profibrotic environment. Moreover, we discuss the impact of senescent alveolar epithelial progenitors, alveolar type 2 (AT2) cells, and AT2-derived transitional epithelial cells in fibrosis. Emerging evidence indicates that transitional epithelial cells are prone to senescence and, hence, are a new player involved in senescence-associated lung fibrosis. Understanding the complex interplay of cell types and cellular regulatory factors contributing to alveolar epithelial progenitor senescence will be crucial to developing targeted therapies to mitigate their downstream profibrotic sequelae and to promote normal alveolar repair.NEW & NOTEWORTHY With an aging population, lung fibrotic diseases are becoming a global health burden. Dysfunctional repair of the alveolar epithelium is a key causative process that initiates lung fibrosis. Normal alveolar regeneration relies on functional progenitor cells; however, the senescence of these cells, which increases with age, hinders their ability to contribute to repair. Here, we discuss studies on the control and consequence of progenitor cell senescence in fibrosis and opportunities for research.


Assuntos
Células Epiteliais Alveolares , Fibrose Pulmonar Idiopática , Humanos , Idoso , Células Epiteliais Alveolares/metabolismo , Fibrose Pulmonar Idiopática/metabolismo , Senescência Celular , Envelhecimento , Células-Tronco/metabolismo , Células Epiteliais/metabolismo , Pulmão/metabolismo
8.
Am J Transplant ; 22(2): 565-573, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34464505

RESUMO

Despite the common detection of non-donor specific anti-HLA antibodies (non-DSAs) after lung transplantation, their clinical significance remains unclear. In this retrospective single-center cohort study of 325 lung transplant recipients, we evaluated the association between donor-specific HLA antibodies (DSAs) and non-DSAs with subsequent CLAD development. DSAs were detected in 30% of recipients and were associated with increased CLAD risk, with higher HRs for both de novo and high MFI (>5000) DSAs. Non-DSAs were detected in 56% of recipients, and 85% of DSA positive tests had concurrent non-DSAs. In general, non-DSAs did not increase CLAD risk in multivariable models accounting for DSAs. However, non-DSAs in conjunction with high BAL CXCL9 levels were associated with increased CLAD risk. Multivariable proportional hazards models demonstrate the importance of the HLA antibody-CXCL9 interaction: CLAD risk increases when HLA antibodies (both DSAs and non-DSAs) are detected in conjunction with high CXCL9. Conversely, CLAD risk is not increased when HLA antibodies are detected with low CXCL9. This study supports the potential utility of BAL CXCL9 measurement as a biomarker to risk stratify HLA antibodies for future CLAD. The ability to discriminate between high versus low-risk HLA antibodies may improve management by allowing for guided treatment decisions.


Assuntos
Antígenos HLA , Transplante de Pulmão , Aloenxertos , Biomarcadores , Quimiocina CXCL9 , Estudos de Coortes , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Humanos , Isoanticorpos , Transplante de Pulmão/efeitos adversos , Prognóstico , Estudos Retrospectivos , Doadores de Tecidos
9.
MMWR Morb Mortal Wkly Rep ; 71(6): 217-223, 2022 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-35143466

RESUMO

In mid-December 2021, the B.1.1.529 (Omicron) variant of SARS-CoV-2, the virus that causes COVID-19, surpassed the B.1.617.2 (Delta) variant as the predominant strain in California.§ Initial reports suggest that the Omicron variant is more transmissible and resistant to vaccine neutralization but causes less severe illness compared with previous variants (1-3). To describe characteristics of patients hospitalized with SARS-CoV-2 infection during periods of Delta and Omicron predominance, clinical characteristics and outcomes were retrospectively abstracted from the electronic health records (EHRs) of adults aged ≥18 years with positive reverse transcription-polymerase chain reaction (RT-PCR) SARS-CoV-2 test results admitted to one academic hospital in Los Angeles, California, during July 15-September 23, 2021 (Delta predominant period, 339 patients) and December 21, 2021-January 27, 2022 (Omicron predominant period, 737 patients). Compared with patients during the period of Delta predominance, a higher proportion of adults admitted during Omicron predominance had received the final dose in a primary COVID-19 vaccination series (were fully vaccinated) (39.6% versus 25.1%), and fewer received COVID-19-directed therapies. Although fewer required intensive care unit (ICU) admission and invasive mechanical ventilation (IMV), and fewer died while hospitalized during Omicron predominance, there were no significant differences in ICU admission or IMV when stratified by vaccination status. Fewer fully vaccinated Omicron-period patients died while hospitalized (3.4%), compared with Delta-period patients (10.6%). Among Omicron-period patients, vaccination was associated with lower likelihood of ICU admission, and among adults aged ≥65 years, lower likelihood of death while hospitalized. Likelihood of ICU admission and death were lowest among adults who had received a booster dose. Among the first 131 Omicron-period hospitalizations, 19.8% of patients were clinically assessed as admitted for non-COVID-19 conditions. Compared with adults considered likely to have been admitted because of COVID-19, these patients were younger (median age = 38 versus 67 years) and more likely to have received at least one dose of a COVID-19 vaccine (84.6% versus 61.0%). Although 20% of SARS-CoV-2-associated hospitalizations during the period of Omicron predominance might be driven by non-COVID-19 conditions, large numbers of hospitalizations place a strain on health systems. Vaccination, including a booster dose for those who are fully vaccinated, remains critical to minimizing risk for severe health outcomes among adults with SARS-CoV-2 infection.


Assuntos
COVID-19/epidemiologia , COVID-19/virologia , Hospitalização/estatística & dados numéricos , SARS-CoV-2 , Vacinação/estatística & dados numéricos , Adulto , Idoso , Feminino , Humanos , Los Angeles/epidemiologia , Masculino , Pessoa de Meia-Idade , Gravidade do Paciente
10.
Am J Respir Crit Care Med ; 203(6): 707-717, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-32991815

RESUMO

Rationale: Idiopathic pulmonary fibrosis (IPF) is an insidious and fatal interstitial lung disease associated with declining pulmonary function. Accelerated aging, loss of epithelial progenitor cell function and/or numbers, and cellular senescence are implicated in the pathogenies of IPF.Objectives: We sought to investigate the role of alveolar type 2 (AT2) cellular senescence in initiation and/or progression of pulmonary fibrosis and therapeutic potential of targeting senescence-related pathways and senescent cells.Methods: Epithelial cells of 9 control donor proximal and distal lung tissues and 11 IPF fibrotic lung tissues were profiled by single-cell RNA sequencing to assesses the contribution of epithelial cells to the senescent cell fraction for IPF. A novel mouse model of conditional AT2 cell senescence was generated to study the role of cellular senescence in pulmonary fibrosis.Measurements and Main Results: We show that AT2 cells isolated from IPF lung tissue exhibit characteristic transcriptomic features of cellular senescence. We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis. We establish that senescence rather than loss of AT2 cells promotes progressive fibrosis and show that either genetic or pharmacologic interventions targeting p53 activation or senescence block fibrogenesis.Conclusions: Senescence of AT2 cells is sufficient to drive progressive pulmonary fibrosis. Early attenuation of senescence-related pathways and elimination of senescent cells are promising therapeutic approaches to prevent pulmonary fibrosis.


Assuntos
Envelhecimento/patologia , Células Epiteliais Alveolares/patologia , Senescência Celular , Fibrose Pulmonar Idiopática/patologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino
11.
Am J Respir Crit Care Med ; 202(11): 1540-1550, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32692579

RESUMO

Rationale: Declining lung function in patients with interstitial lung disease is accompanied by epithelial remodeling and progressive scarring of the gas-exchange region. There is a need to better understand the contribution of basal cell hyperplasia and associated mucosecretory dysfunction to the development of idiopathic pulmonary fibrosis (IPF).Objectives: We sought to decipher the transcriptome of freshly isolated epithelial cells from normal and IPF lungs to discern disease-dependent changes within basal stem cells.Methods: Single-cell RNA sequencing was used to map epithelial cell types of the normal and IPF human airways. Organoid and air-liquid interface cultures were used to investigate functional properties of basal cell subtypes.Measurements and Main Results: We found that basal cells included multipotent and secretory primed subsets in control adult lung tissue. Secretory primed basal cells include an overlapping molecular signature with basal cells obtained from the distal lung tissue of IPF lungs. We confirmed that NOTCH2 maintains undifferentiated basal cells and restricts basal-to-ciliated differentiation, and we present evidence that NOTCH3 functions to restrain secretory differentiation.Conclusions: Basal cells are dynamically regulated in disease and are specifically biased toward the expansion of the secretory primed basal cell subset in IPF. Modulation of basal cell plasticity may represent a relevant target for therapeutic intervention in IPF.


Assuntos
Plasticidade Celular , Proliferação de Células/genética , Autorrenovação Celular/genética , Células Epiteliais/citologia , Fibrose Pulmonar Idiopática/genética , Mucosa Respiratória/citologia , Idoso , Células Epiteliais Alveolares/citologia , Células Epiteliais Alveolares/metabolismo , Membrana Basal , Estudos de Casos e Controles , Células Epiteliais/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Masculino , Pessoa de Meia-Idade , RNA-Seq , Mucosa Respiratória/metabolismo , Análise de Célula Única , Transcriptoma , Adulto Jovem
13.
Thorax ; 75(1): 78-80, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31611341

RESUMO

In this retrospective study of a randomised trial of simtuzumab in idiopathic pulmonary fibrosis (IPF), prodromal decline in forced vital capacity (FVC) was significantly associated with increased risk of mortality, respiratory and all-cause hospitalisations, and categorical disease progression. Predictive modelling of progression-free survival event risk was used to assess the effect of population enrichment for patients at risk of rapid progression of IPF; C-index values were 0.64 (death), 0.69 (disease progression), and 0.72 (adjudicated respiratory hospitalisation) and 0.76 (all-cause hospitalisation). Predictive modelling may be a useful tool for improving efficiency of clinical trials with categorical end points.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/fisiopatologia , Idoso , Ensaios Clínicos Fase II como Assunto , Progressão da Doença , Feminino , Humanos , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Testes de Função Respiratória , Estudos Retrospectivos , Fatores de Risco , Falha de Tratamento
14.
Int J Mol Sci ; 21(7)2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-32218238

RESUMO

: Alveolar epithelial type II cells (AT2) are a heterogeneous population that have critical secretory and regenerative roles in the alveolus to maintain lung homeostasis. However, impairment to their normal functional capacity and development of a pro-fibrotic phenotype has been demonstrated to contribute to the development of idiopathic pulmonary fibrosis (IPF). A number of factors contribute to AT2 death and dysfunction. As a mucosal surface, AT2 cells are exposed to environmental stresses that can have lasting effects that contribute to fibrogenesis. Genetical risks have also been identified that can cause AT2 impairment and the development of lung fibrosis. Furthermore, aging is a final factor that adds to the pathogenic changes in AT2 cells. Here, we will discuss the homeostatic role of AT2 cells and the studies that have recently defined the heterogeneity of this population of cells. Furthermore, we will review the mechanisms of AT2 death and dysfunction in the context of lung fibrosis.


Assuntos
Células Epiteliais Alveolares , Fibrose Pulmonar Idiopática , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Animais , Morte Celular , Autorrenovação Celular , Fibroblastos , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Transdução de Sinais
15.
Am J Respir Cell Mol Biol ; 60(1): 41-48, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30130411

RESUMO

Severe pulmonary fibrosis such as idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of extracellular matrix and fibroblast activation. Targeting fibroblast activation has contributed to the development of antifibrotic therapeutics for patients with IPF. Mitogen-activated protein kinase-activated protein kinase 2 (MK2), downstream in the transforming growth factor-ß/p38 mitogen-activated protein kinase pathway, has been implicated in inflammatory and fibrosing diseases. Increased concentrations of activated MK2 were expressed in IPF lung and in the mouse bleomycin model of lung fibrosis. The aim of the present study was to determine the role and the mechanisms of MK2 in fibroblast invasion and lung fibrosis. Our results showed that an MK2 inhibitor (MMI-0100) was able to inhibit the invasive capacity of lung fibroblasts isolated from patients with IPF, as well as fibroblasts isolated from both wild-type mice and mice with overexpressing hyaluronan synthase 2 (HAS2) in the myofibroblast compartment. We previously showed that hyaluronan and HAS2 regulate fibroblast invasion and lung fibrosis in vivo. The results of the present study showed that MMI-0100 reduced transforming growth factor-ß-induced hyaluronan production in human and mouse fibroblasts in vitro and that HAS2 mediated MK2 activation, suggesting a feed-forward loop in fibroblast activation. More importantly, MK2 inhibition attenuated hyaluronan accumulation and reduced collagen content in bleomycin-injured mouse lungs in vivo. Conditional deletion of MK2 in fibroblasts attenuated bleomycin-induced lung fibrosis. These data provide evidence that MK2 has a role in fibroblast invasion and fibrosis and may be a novel therapeutic target in pulmonary fibrosis.


Assuntos
Fibroblastos/patologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Fibrose Pulmonar/prevenção & controle , Índice de Gravidade de Doença , Animais , Antibióticos Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Bleomicina/toxicidade , Células Cultivadas , Fibroblastos/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia
17.
Respir Res ; 20(1): 55, 2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30866942

RESUMO

Data from controlled clinical studies in patients with more advanced idiopathic pulmonary fibrosis (IPF) could inform clinical practice, but they are limited, since this sub-population is usually excluded from clinical trials. These exploratory post-hoc analyses of the open-label, long-term extension study RECAP (NCT00662038) aimed to assess the efficacy and safety of pirfenidone in patients with more advanced IPF. Patients were categorised according to the extent of lung function impairment at baseline: more advanced (percent predicted FVC <50% and/or DLco <35%) and less advanced (percent predicted FVC ≥50% and DLco ≥35%).Overall, 596 patients with baseline FVC and/or DLco values available were included in the analyses; 187 patients had more advanced disease, and 409 patients had less advanced disease. Mean percent predicted FVC declined throughout 180 weeks of treatment in both more and less advanced disease subgroups. Both subgroups exhibited a similar pattern of adverse events; however, adverse events related to IPF progression were experienced by a higher proportion of patients with more advanced versus less advanced disease. Discontinuation rates due to any reason, adverse events related to IPF progression, or deaths were each higher in the more advanced versus the less advanced disease subgroup.These analyses found that longer-term pirfenidone treatment resulted in a similar rate of lung function decline and safety profile in patients with more advanced versus less advanced IPF, and the data suggest that pirfenidone is efficacious, well tolerated, and a feasible treatment option in patients with more advanced IPF.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Progressão da Doença , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Piridonas/uso terapêutico , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
18.
Am J Respir Crit Care Med ; 197(11): 1443-1456, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29634284

RESUMO

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung remodeling, which progressively abolishes lung function in an RTK (receptor tyrosine kinase)-dependent manner. Gas6 (growth arrest-specific 6) ligand, Tyro3 (TYRO3 protein tyrosine kinase 3), and Axl (anexelekto) RTK expression and activity are increased in IPF. OBJECTIVES: To determine if targeting these RTK pathways would inhibit fibroblast activation and the development of pulmonary fibrosis. METHODS: Quantitative genomic, proteomic, and functional analyses were used to determine Gas6/TAM (Tyro3, Axl, and Mertk [MER proto-oncogene, tyrosine kinase]) RTK expression and activation in tissues and fibroblasts from normal and IPF lungs. The profibrotic impact of these RTK pathways were also examined in bleomycin-induced pulmonary fibrosis and in SCID/Bg mice that developed pulmonary fibrosis after the intravenous administration of primary IPF fibroblasts. MEASUREMENTS AND MAIN RESULTS: Gas6, Axl, and Tyro3 were increased in both rapidly and slowly progressive IPF compared with normal lung samples and fibroblasts. Targeting these pathways with either specific antibodies directed at Gas6 or Axl, or with small-molecule TAM inhibitors indicated that the small molecule-mediated targeting approach was more efficacious in both in vitro and in vivo studies. Specifically, the TAM receptor inhibitor R428 (also known as BGB324) significantly inhibited the synthetic, migratory, and proliferative properties of IPF fibroblasts compared with the other Gas6/TAM receptor targeting agents. Finally, loss of Gas6 expression decreased lung fibrotic responses to bleomycin and treatment with R428 inhibited pulmonary fibrosis in humanized SCID/Bg mice. CONCLUSIONS: Gas6/TAM receptor activity contributes to the activation of pulmonary fibroblasts in IPF, suggesting that targeting this RTK pathway might be an effective antifibrotic strategy in this disease.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/efeitos dos fármacos , Antibióticos Antineoplásicos/uso terapêutico , Bleomicina/uso terapêutico , Fibroblastos/efeitos dos fármacos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/genética , Proteínas de Membrana/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células/efeitos dos fármacos , Humanos , Fibrose Pulmonar Idiopática/fisiopatologia , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Proto-Oncogene Mas , Transdução de Sinais/genética
19.
Physiol Rev ; 91(1): 221-64, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21248167

RESUMO

Accumulation and turnover of extracellular matrix components are the hallmarks of tissue injury. Fragmented hyaluronan stimulates the expression of inflammatory genes by a variety of immune cells at the injury site. Hyaluronan binds to a number of cell surface proteins on various cell types. Hyaluronan fragments signal through both Toll-like receptor (TLR) 4 and TLR2 as well as CD44 to stimulate inflammatory genes in inflammatory cells. Hyaluronan is also present on the cell surface of epithelial cells and provides protection against tissue damage from the environment by interacting with TLR2 and TLR4. Hyaluronan and hyaluronan-binding proteins regulate inflammation, tissue injury, and repair through regulating inflammatory cell recruitment, release of inflammatory cytokines, and cell migration. This review focuses on the role of hyaluronan as an immune regulator in human diseases.


Assuntos
Ácido Hialurônico/imunologia , Sistema Imunitário/metabolismo , Animais , Artrite/metabolismo , Lesões Encefálicas/metabolismo , Diabetes Mellitus/metabolismo , Cardiopatias/metabolismo , Humanos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/biossíntese , Hialuronoglucosaminidase/metabolismo , Nefropatias/metabolismo , Hepatopatias/metabolismo , Pneumopatias/metabolismo , Transdução de Sinais , Células-Tronco/metabolismo , Receptores Toll-Like/metabolismo , Ferimentos e Lesões/metabolismo
20.
Annu Rev Med ; 67: 487-95, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26565677

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal disease that has long eluded therapy. Prognosis remains very poor, and currently lung transplantation offers the only hope of survival. Recently, great strides have been made in the development of pharmaceutical therapy to treat IPF. Pirfenidone, an oral antifibrotic agent, has been shown to slow progression of the disease and improve progression-free survival, offering new hope for patients suffering from IPF.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Piridonas/uso terapêutico , Anti-Inflamatórios não Esteroides/farmacologia , Progressão da Doença , Intervalo Livre de Doença , Humanos , Piridonas/farmacologia
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