Evidence of eosinophil extracellular trap cell death in COPD: does it represent the trigger that switches on the disease?

In spite of the numerous studies on chronic obstructive pulmonary disease (COPD), the cellular and molecular basis of the disease's development remain unclear. Neutrophils and eosinophils are known to be key players in COPD. Recently, neutrophil extracellular trap cell death (NETosis), a mechanism due to decondensation and extrusion of chromatin to form extracellular traps, has been demonstrated in COPD. However, there is limited knowledge about eosinophil extracellular trap cell death (EETosis) and its role in the pathogenesis of COPD. The aim of this study was to evaluate EETosis in stable COPD. Induced sputum obtained from healthy smokers and low exacerbation risk COPD A or B group patients or high exacerbation risk COPD C or D group patients were included. Samples were examined using electron microscopy and immunofluorescence. Healthy smokers (n=10) and COPD A (n=19) group exhibited neutrophilic or paucigranulocytic phenotypes, with NETosis being absent in these patients. In contrast, COPD B (n=29), with eosinophilic or mixed phenotypes, showed EETosis and incipient NETosis. COPD C (n=18) and COPD D groups (n=13) were differentiated from low exacerbation rate-COPD group by the abundant cellular debris, with COPD C group having an eosinophilic pattern and numerous cells undergoing EETosis. A hallmark of this group was the abundant released membranes that often appeared phagocytosed by neutrophils, which coincidentally exhibited early NETosis changes. The COPD D group included patients with a neutrophilic or mixed pattern, with abundant neutrophil extracellular trap-derived material. This study is the first to demonstrate EETosis at different stages of stable COPD. The results suggest a role for eosinophils in COPD pathophysiology, especially at the beginning and during the persistence of the disease, regardless of whether the patient quit smoking, with EETosis debris probably triggering uncontrolled NETosis. The main target of these findings should be young smokers with the potential to develop COPD.

Diagrama A-D GOLD 2011 bajo el microscopio: Respondiendo a la fisiopatogénia de la EPOC con implicancias en el manejo de la enfermedad / GOLD 2011 A-D CHART under the microscope. Responding to COPD physiopathogeny with implications in disease management

El objetivo de este trabajo fue analizar el fenotipo celular en esputo de los pacientes con diagnóstico de EPOC clasificados según el diagrama A-D. Se reclutaron paciente ambos géneros, edad ≥ 60 años, ex fumadores de por lo menos 10 pack/año, con diagnóstico de EPOC en situación estable. Se los clasifico según GOLD 2011 en categorías clínicas A, B, C, D y se les analizó el patrón inflamatorio bronquial por medio de citología de esputo. Se estudiaron 85 pacientes con diagnóstico de EPOC distribuidos en categoría A (19), B (29), C (19) y D (18); la edad de estos últimos fue significativamente mayor que las del resto de los pacientes. El patrón predominante celular en esputo fue Eosinofílico (43), Neutrofílico (17), Mixto (9) y Paucigranulocítico (16). La distribución del patrón celular predominante en relación a cada grupo clínico de EPOC fue estadísticamente significativo p ≤ 0,001. El fenotipo celular Neutrofílico en el grupo A; eosinofílico y mixto en los grupos B y C y en el grupo D, aun presentes los eosinófilos predominó el patrón Neutrofílico. Concluimos que este estudio identificó patrones celulares inflamatorios que caracterizan cada grupo del diagrama A-D de la EPOC lo cual puede contribuir a explicar su carácter heterogéneo, personalizar el tratamiento y especialmente apunta a identificar tempranamente el paciente en riesgo de iniciar y perpetuar la enfermedad.

GOLD 2011 A-D CHART under the microscope: Responding to COPD physiopathogeny with implications in disease management

The purpose of this study was to analyze sputum cellular phenotype in patients with a diagnosis of COPD classified according to the A-D chart. We included patients of both genders, aged ≥ 60 years, who were former smokers of at least 10 packets/year, with a diagnosis of COPD under stable conditions. They were classified according to the 2011 GOLD criteria into clinical categories A, B, C, D and their bronchial inflammatory pattern was analyzed using sputum cytology. Eighty-five patients with a diagnosis of COPD were divided into category A (19), B (29), C (19) and D (18); the age of the latter was significantly higher than the rest of the patients. The predominant cellular pattern in sputum was eosinophilic (43), neutrophilic (17), mixed (9) and paucigranulocytic (16). The distribution of the predominant cellular pattern in connection with each COPD clinical group was statistically significant p ≤ 0.001. The neutrophilic cellular phenotype was predominant in group A; the eosinophilic and mixed phenotypes in groups B and C, and in group D, even though eosinophils were present, the predominant pattern was neutrophilic. We concluded that this study identified inflammatory cellular patterns that distinguish each group in the COPD A-D chart, which can contribute to explain their heterogeneous nature, customize treatment and, most of all, identify patients at risk of disease onset and perpetuation at an early stage.