RESUMO
OBJECTIVE: Lymphangioleiomyomatosis (LAM) is a rare, destructive disease of the lungs with a limited number of determinants of disease activity, which are a critical need for clinical trials. FGF23 has been implicated in several chronic pulmonary diseases. We aimed to determine the association between serum FGF23 levels and pulmonary function in a cohort of patients with LAM. METHODS: This was a descriptive single-center study in which subjects with LAM and controls with unreported lung disease were recruited. Serum FGF23 levels were measured in all subjects. Clinical data, including pulmonary function testing, were retrospectively obtained from electronic medical records of LAM subjects. Associations between FGF23 levels and clinical features of LAM were explored via nonparametric hypothesis testing. RESULTS: The sample comprised 37 subjects with LAM and 16 controls. FGF23 levels were higher in the LAM group than in the control group. In the LAM group, FGF23 levels above the optimal cutoff point distinguished 33% of the subjects who had nondiagnostic VEGF-D levels. Lower FGF23 levels were associated with impaired DLCO (p = 0.04), particularly for those with isolated diffusion impairment with no other spirometric abnormalities (p = 0.04). CONCLUSIONS: Our results suggest that FGF23 is associated with pulmonary diffusion abnormalities in LAM patients and elicit novel mechanisms of LAM pathogenesis. FGF23 alone or in combination with other molecules needs to be validated as a biomarker of LAM activity in future clinical research.
Assuntos
Pneumopatias , Neoplasias Pulmonares , Linfangioleiomiomatose , Humanos , Linfangioleiomiomatose/complicações , Linfangioleiomiomatose/diagnóstico , Linfangioleiomiomatose/patologia , Estudos Retrospectivos , Pneumopatias/complicações , Biomarcadores , Pulmão , Neoplasias Pulmonares/complicaçõesRESUMO
ABSTRACT Objective: Lymphangioleiomyomatosis (LAM) is a rare, destructive disease of the lungs with a limited number of determinants of disease activity, which are a critical need for clinical trials. FGF23 has been implicated in several chronic pulmonary diseases. We aimed to determine the association between serum FGF23 levels and pulmonary function in a cohort of patients with LAM. Methods: This was a descriptive single-center study in which subjects with LAM and controls with unreported lung disease were recruited. Serum FGF23 levels were measured in all subjects. Clinical data, including pulmonary function testing, were retrospectively obtained from electronic medical records of LAM subjects. Associations between FGF23 levels and clinical features of LAM were explored via nonparametric hypothesis testing. Results: The sample comprised 37 subjects with LAM and 16 controls. FGF23 levels were higher in the LAM group than in the control group. In the LAM group, FGF23 levels above the optimal cutoff point distinguished 33% of the subjects who had nondiagnostic VEGF-D levels. Lower FGF23 levels were associated with impaired DLCO (p = 0.04), particularly for those with isolated diffusion impairment with no other spirometric abnormalities (p = 0.04). Conclusions: Our results suggest that FGF23 is associated with pulmonary diffusion abnormalities in LAM patients and elicit novel mechanisms of LAM pathogenesis. FGF23 alone or in combination with other molecules needs to be validated as a biomarker of LAM activity in future clinical research.
RESUMO Objetivo: A linfangioleiomiomatose (LAM) é uma doença rara e destrutiva dos pulmões com um número limitado de determinantes da atividade da doença, que são uma necessidade crítica para ensaios clínicos. O FGF23 já foi implicado em várias doenças pulmonares crônicas. O nosso objetivo foi determinar a associação entre os níveis séricos de FGF23 e a função pulmonar em uma coorte de pacientes com LAM. Métodos: Estudo descritivo unicêntrico no qual foram recrutados indivíduos com LAM e controles com doenças pulmonares não declaradas. Os níveis séricos de FGF23 foram medidos em todos os indivíduos. Os dados clínicos, incluindo testes de função pulmonar, foram obtidos retrospectivamente a partir dos prontuários eletrônicos dos indivíduos com LAM. As associações entre os níveis de FGF23 e as características clínicas da LAM foram exploradas por meio do teste de hipóteses não paramétrico. Resultados: A amostra incluiu 37 indivíduos com LAM e 16 controles. Os níveis de FGF23 foram mais altos no grupo LAM do que no grupo controle. No grupo LAM, níveis de FGF23 acima do ponto de corte ideal distinguiram 33% dos indivíduos com níveis não diagnósticos de VEGF-D. Níveis mais baixos de FGF23 estavam associados à DLCO comprometida (p = 0,04), particularmente naqueles com comprometimento isolado da difusão e sem outras alterações espirométricas (p = 0,04). Conclusões: Nossos resultados sugerem que o FGF23 está associado a alterações na difusão pulmonar em pacientes com LAM e potencialmente indicam novos mecanismos de patogênese da LAM. O FGF23 isoladamente ou em combinação com outras moléculas precisa ser validado como um biomarcador da atividade da LAM em futuras pesquisas clínicas.
RESUMO
The prevalence of clinically evident interstitial lung disease in patients with rheumatoid arthritis is approximately 10%. An additional 33% of undiagnosed patients have interstitial lung abnormalities that can be detected with high-resolution computed tomography. Rheumatoid arthritis-interstitial lung disease patients have three times the risk of death compared to those with rheumatoid arthritis occurring in the absence of interstitial lung disease, and the mortality related to interstitial lung disease is rising. Rheumatoid arthritis-interstitial lung disease is most commonly classified as the usual interstitial pneumonia pattern, overlapping mechanistically and phenotypically with idiopathic pulmonary fibrosis, but can occur in a non-usual interstitial pneumonia pattern, mainly nonspecific interstitial pneumonia. Based on this, we propose two possible pathways to explain the coexistence of rheumatoid arthritis and interstitial lung disease: (i) Rheumatoid arthritis-interstitial lung disease with a non-usual interstitial pneumonia pattern may come about when an immune response against citrullinated peptides taking place in another site (e.g. the joints) subsequently affects the lungs; (ii) Rheumatoid arthritis-interstitial lung disease with a usual interstitial pneumonia pattern may represent a disease process in which idiopathic pulmonary fibrosis-like pathology triggers an immune response against citrullinated proteins that promotes articular disease indicative of rheumatoid arthritis. More studies focused on elucidating the basic mechanisms leading to different sub-phenotypes of rheumatoid arthritis-interstitial lung disease and the overlap with idiopathic pulmonary fibrosis are necessary to improve our understanding of the disease process and to define new therapeutic targets.
Assuntos
Artrite Reumatoide/complicações , Fibrose Pulmonar Idiopática/etiologia , Doenças Pulmonares Intersticiais/etiologia , Artrite Reumatoide/patologia , Humanos , Fibrose Pulmonar Idiopática/epidemiologia , Fibrose Pulmonar Idiopática/patologia , Doenças Pulmonares Intersticiais/epidemiologia , Doenças Pulmonares Intersticiais/patologia , Fenótipo , Prevalência , Tomografia Computadorizada por Raios XRESUMO
RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by epithelial phenotypic changes and fibroblast activation. Based on the temporal heterogeneity of IPF, we hypothesized that hyperplastic alveolar epithelial cells regulate the fibrotic response. OBJECTIVES: To identify novel mediators of fibrosis comparing the transcriptional signature of hyperplastic epithelial cells and conserved epithelial cells in the same lung. METHODS: Laser capture microscope and microarrays analysis were used to identify differentially expressed genes in IPF lungs. Bleomycin-induced lung fibrosis was evaluated in Mmp19-deficient and wild-type (WT) mice. The role of matrix metalloproteinase (MMP)-19 was additionally studied by transfecting the human MMP19 in alveolar epithelial cells. MEASUREMENTS AND MAIN RESULTS: Laser capture microscope followed by microarray analysis revealed a novel mediator, MMP-19, in hyperplastic epithelial cells adjacent to fibrotic regions. Mmp19(-/-) mice showed a significantly increased lung fibrotic response to bleomycin compared with WT mice. A549 epithelial cells transfected with human MMP19 stimulated wound healing and cell migration, whereas silencing MMP19 had the opposite effect. Gene expression microarray of transfected A549 cells showed that PTGS2 (prostaglandin-endoperoxide synthase 2) was one of the highly induced genes. PTGS2 was overexpressed in IPF lungs and colocalized with MMP-19 in hyperplastic epithelial cells. In WT mice, PTGS2 was significantly increased in bronchoalveolar lavage and lung tissues after bleomycin-induced fibrosis, but not in Mmp19(-/-) mice. Inhibition of Mmp-19 by siRNA resulted in inhibition of Ptgs2 at mRNA and protein levels. CONCLUSIONS: Up-regulation of MMP19 induced by lung injury may play a protective role in the development of fibrosis through the induction of PTGS2.