RESUMO
OBJECTIVE: Lung transplant for acute respiratory distress syndrome in patients supported with extracorporeal membrane oxygenation was rare before 2020, but was rapidly adopted to rescue patients with COVID-19 with lung failure. This study aims to compare the outcomes of patients who underwent lung transplant for COVID-associated acute respiratory distress syndrome and non-COVID acute respiratory distress syndrome, and to assess the impact of type and duration of extracorporeal membrane oxygenation support on survival. METHODS: Using the United Network for Organ Sharing database, we identified 311 patients with acute respiratory distress syndrome who underwent lung transplant from 2007 to 2022 and performed a retrospective analysis of the patients who required extracorporeal membrane oxygenation preoperatively, stratified by COVID-associated acute respiratory distress syndrome and non-COVID acute respiratory distress syndrome listing diagnoses. The primary outcome was 1-year survival. Secondary outcomes included the effect of type and duration of extracorporeal membrane oxygenation on survival. RESULTS: During the study period, 236 patients with acute respiratory distress syndrome and preoperative extracorporeal membrane oxygenation underwent lung transplant; 181 patients had a listing diagnosis of COVID-associated acute respiratory distress syndrome (77%), and 55 patients had a listing diagnosis of non-COVID acute respiratory distress syndrome (23%). Patients with COVID-associated acute respiratory distress syndrome were older, were more likely to be female, had higher body mass index, and spent longer on the waitlist (all P < .02) than patients with non-COVID acute respiratory distress syndrome. The 2 groups had similar 1-year survival (85.8% vs 81.1%, P = .2) with no differences in postoperative complications. Patients with COVID-associated acute respiratory distress syndrome required longer times on extracorporeal membrane oxygenation pretransplant (P = .02), but duration of extracorporeal membrane oxygenation support was not a predictor of 1-year survival (P = .2). CONCLUSIONS: Despite prolonged periods of pretransplant extracorporeal membrane oxygenation support, selected patients with acute respiratory distress syndrome can undergo lung transplant safely with acceptable short-term outcomes. Appropriate selection criteria and long-term implications require further analysis.
Assuntos
COVID-19 , Oxigenação por Membrana Extracorpórea , Transplante de Pulmão , Síndrome do Desconforto Respiratório , Humanos , Oxigenação por Membrana Extracorpórea/mortalidade , COVID-19/complicações , COVID-19/mortalidade , Transplante de Pulmão/mortalidade , Transplante de Pulmão/efeitos adversos , Feminino , Masculino , Pessoa de Meia-Idade , Síndrome do Desconforto Respiratório/terapia , Síndrome do Desconforto Respiratório/mortalidade , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/diagnóstico , Estudos Retrospectivos , Resultado do Tratamento , Adulto , Fatores de Tempo , Idoso , SARS-CoV-2 , Fatores de RiscoRESUMO
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.
Assuntos
Ciclo-Oxigenase 2/metabolismo , Fibrose Pulmonar Idiopática/enzimologia , Metaloproteinases da Matriz Secretadas/metabolismo , Animais , Bleomicina , Células Cultivadas , Células Epiteliais/metabolismo , Regulação Enzimológica da Expressão Gênica , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/patologia , Microdissecção e Captura a Laser , Metaloproteinases da Matriz Secretadas/genética , Camundongos , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Alvéolos Pulmonares/metabolismo , Regulação para CimaRESUMO
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disorder characterized by fibroproliferation and excessive accumulation of extracellular matrix in the lung. METHODS AND FINDINGS: Using oligonucleotide arrays, we identified osteopontin as one of the genes that significantly distinguishes IPF from normal lungs. Osteopontin was localized to alveolar epithelial cells in IPF lungs and was also significantly elevated in bronchoalveolar lavage from IPF patients. To study the fibrosis-relevant effects of osteopontin we stimulated primary human lung fibroblasts and alveolar epithelial cells (A549) with recombinant osteopontin. Osteopontin induced a significant increase of migration and proliferation in both fibroblasts and epithelial cells. Epithelial growth was inhibited by the pentapeptide Gly-Arg-Gly-Asp-Ser (GRGDS) and antibody to CD44, while fibroproliferation was inhibited by GRGDS and antibody to alphavbeta3 integrin. Fibroblast and epithelial cell migration were inhibited by GRGDS, anti-CD44, and anti-alphavbeta3. In fibroblasts, osteopontin up-regulated tissue inhibitor of metalloprotease-1 and type I collagen, and down-regulated matrix metalloprotease-1 (MMP-1) expression, while in A549 cells it caused up-regulation of MMP-7. In human IPF lungs, osteopontin colocalized with MMP-7 in alveolar epithelial cells, and application of weakest link statistical models to microarray data suggested a significant interaction between osteopontin and MMP-7. CONCLUSIONS: Our results provide a potential mechanism by which osteopontin secreted from the alveolar epithelium may exert a profibrotic effect in IPF lungs and highlight osteopontin as a potential target for therapeutic intervention in this incurable disease.