Multifaceted mechanisms in COPD: inflammation, immunity, and tissue repair and destruction

Chung, Kian Fan; Adcock, Ian M.

doi:10.1183/09031936.00018908

Cited by 518 publications

(473 citation statements)

References 304 publications

(319 reference statements)

Supporting

Mentioning

435

Contrasting

Unclassified

Order By: Relevance

“…In addition, we confirmed that the% predicted post bronchodilator FEV1 was inversely correlated to the proportion of neutrophils [23,25,35]. It suggests that neutrophilic inflammation is an important factor in the pathogenesis of irreversible airflow limitation in COPD [5]. On the other hand, high sputum neutrophil count may reflect constant activation of local innate immunity in response to bacterial colonization developing in remodelled and altered airways [20].…”

Section: Discussionsupporting

confidence: 70%

Local and systemic cellular inflammation and cytokine release in chronic obstructive pulmonary disease

Moermans¹,

Heinen

Nguyen

et al. 2011

Cytokine

View full text Add to dashboard Cite

Background: Chronic obstructive pulmonary disease (COPD) is a chronic airway inflammatory disease caused by repeated exposure to noxious gases or particles. It is now recognized that the disease also features systemic inflammation. The purpose of our study was to compare airway and systemic inflammation in COPD to that seen in healthy subjects and to relate the inflammation with the disease severity. Methods: Ninety-five COPD patients, encompassing the whole severity spectrum of the disease, were recruited from our outpatient clinic and rehabilitation center and compared to 33 healthy subjects. Induced sputum and blood samples were obtained for measurement of inflammatory cell count. Interleukin (IL)-4, IL-6, IL-10, TNF-α and IFN-γ produced by 24 h sputum and blood cell cultures were measured. Results: Compared to healthy subjects, COPD exhibited a prominent airway neutrophilic inflammation associated with a marked IL-10, IL-6 and TNF-α release deficiency that contrasted with a raised IFN-γ production. Neutrophilic inflammation was also prominent at blood level together with raised production of IFN-γ, IL-10 and TNF-α. Furthermore, sputum neutrophilia correlated with disease severity assessed by GOLD stages. Likewise the extent of TNF-α release from blood cells also positively correlated with the disease severity but negatively with that of sputum cell culture. Blood release of TNF-α and IL-6 negatively correlated with body mass index. Altogether, our results showed a significant relationship between cellular marker in blood and sputum but poor relationship between local and systemic release of cytokines. Conclusions: COPD is characterized by prominent neutrophilic inflammation and raised IFN-γ production at both bronchial and systemic level. Overproduction of TNF-α at systemic level correlates with disease severity and inversely with body mass index.

show abstract

Section: Discussionsupporting

confidence: 70%

Local and systemic cellular inflammation and cytokine release in chronic obstructive pulmonary disease

Moermans¹,

Heinen

Nguyen

et al. 2011

Cytokine

View full text Add to dashboard Cite

show abstract

“…Chronic inflammation in COPD is orchestrated by the activity of cytokines and chemokines, of which many can be detected at increased levels in the circulation of patients [5,23]. In stimulation experiments using endothelial cells that, in vivo, reflect the first responders of the lungs to these proinflammatory signals, we found that IL-1β and TNFα significantly induced the levels of miR-223 in a time-dependent manner.…”

Section: Discussionmentioning

confidence: 77%

“…These factors, among other mechanisms, lead to infiltration of the airway epithelium with inflammatory cells, chronic bronchial inflammation and consecutive tissue destruction [5].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-223 controls the expression of histone deacetylase 2: a novel axis in COPD

et al. 2016

View full text Add to dashboard Cite

Reduced activity of histone deacetylase 2 (HDAC2) has been described in patients with chronic obstructive pulmonary disease (COPD), but the mechanisms resulting in decreased expression of this important epigenetic modifier remain unknown. Here, we employed several in vitro experiments to address the role of microRNAs (miRNAs) on the regulation of HDAC2 in endothelial cells. Manipulation of miRNA levels in human pulmonary artery endothelial cells (HPAEC) was achieved by using electroporation with anti-miRNAs and miRNA mimics. Target prediction software identified miR-223 as a potential repressor of HDAC2. In subsequent stimulation experiments using inflammatory cytokines known to be increased in patients with COPD, miR-223 was found to be significantly induced. Functional analysis demonstrated that overexpression of miR-223 decreased HDAC2 expression and activity in HPAEC. Conversely, HDAC2 expression and activity was preserved in anti-miR-223-treated cells. Direct miRNAtarget interaction was confirmed by reporter gene assay. In a next step, reduced expression of HDAC2 was found to increase the levels of the chemokine fractalkine (CX3CL1). In vivo studies confirmed elevated expression levels of miR-223 in mice exposed to cigarette smoke and in emphysematous lung tissue from LPS-treated mice. Moreover, a significant inverse correlation of miR-223 and HDAC2 expression was found in two independent cohorts of COPD patients. These data emphasize that miR-223, the most prevalent miRNA in COPD, controls expression and activity of HDAC2 in pulmonary cells, which, in turn, might alter the expression profile of chemokines. This pathway provides a novel pathogenic link between dysregulated miRNA expression and epigenetic activity in COPD. KEY MESSAGES: Histone deacetylase 2 is directly targeted by miR-223. Levels of miR-223 are induced by interleukin-1 and tumor necrosis factor-. miR-223 controls the expression of fractalkine by targeting histone deacetylase 2. miR-223 levels are increased in COPD mouse models. miR-223 levels inversely correlate with HDAC2 expression in COPD patients. AbstractReduced activity of Histone Deacetylase 2 (HDAC2) has been described in patients with chronic obstructive pulmonary disease (COPD) but the mechanisms resulting in decreased expression of this important epigenetic modifier remain unknown. Here we employed several in vitro experiments to address the role of microRNAs (miRNAs) on the regulation of HDAC2 in endothelial cells. Manipulation of miRNA levels in human pulmonary artery endothelial cells (HPAEC) was achieved by using electroporation with anti-miRNAs and miRNA mimics.Target prediction software identified miR-223 as a potential repressor of HDAC2. In subsequent stimulation experiments using inflammatory cytokines known to be increased in patients with COPD miR-223 was found to be significantly induced. Functional analysis demonstrated that overexpression of miR-223 decreased HDAC2 expression and activity in HPAEC. Conversely, HDAC2 expression and activity was preserved i...

show abstract

“…O acúmulo de macrófagos nas paredes das vias aéreas e no parênquima pulmonar dos tabagistas que desenvolvem DPOC pode ser explicado tanto pelo prolongamento do tempo de vida da célula no pulmão como pelo aumento do recrutamento de monócitos (seu precursor) da circulação 13 . Alguns trabalhos sugerem que a participação dos macrófagos na patogênese da DPOC tem relação com a sua capacidade de produzir enzimas metaloproteases (MMP) como a MMP-1, MMP-9 e MMP-12 14,15,16,17 . Acredita-se que as metaloproteases sejam capazes de degradar proteínas de forma semelhante às enzimas neutrofílicas 14 e recrutar células inflamatórias da circulação, facilitando sua infiltração nos tecidos lesados 15 .…”

Section: Macrófagosunclassified

“…Alguns trabalhos sugerem que a participação dos macrófagos na patogênese da DPOC tem relação com a sua capacidade de produzir enzimas metaloproteases (MMP) como a MMP-1, MMP-9 e MMP-12 14,15,16,17 . Acredita-se que as metaloproteases sejam capazes de degradar proteínas de forma semelhante às enzimas neutrofílicas 14 e recrutar células inflamatórias da circulação, facilitando sua infiltração nos tecidos lesados 15 . Macró-fagos recolhidos do lavado broncoalveolar (LBA) de pacientes com DPOC apresentam aumento da expressão de receptores para MMP-1 e MMP-9 16 , enquanto que tanto camundongos com deficiência de MMP-12 16 quanto o uso de inibidores de MMP em cobaias 18 apresentam efeito protetor à exposição à fumaça de cigarro.…”

Section: Macrófagosunclassified

Células inflamatórias e seus mediadores na patogênese da DPOC

Costa

Rufino

Silva

2009

Rev. Assoc. Med. Bras.

View full text Add to dashboard Cite

Artigo de revisão ResumoA doença pulmonar obstrutiva crônica (DPOC) é causada por processo inflamatório crônico que limita o fluxo aéreo, sendo sua principal causa o tabagismo. Conforme dados da Organização Mundial de Saúde (OMS), a DPOC será a quarta causa de mortalidade em 2020, atrás apenas das doenças vasculares, cardíacas e cerebral, além das neoplasias. Apesar do enorme crescimento da prevalência e da mortalidade da DPOC, não existe nenhuma terapêutica que consiga controlar a evolução da doença estabelecida. O processo inflamatório crônico causado pelos gases da fumaça de tabaco desencadeia alterações estruturais que predominam nas pequenas vias aéreas (menores que 2 mm). Essa agressão provoca um processo inflamatório que conta com a participação não apenas de macrófagos, linfócitos e neutrófilos, mas células estruturais como epiteliais, musculares e fibroblastos. Atualmente, a interação entre macrófagos e linfócitos, especialmente CD8+, tem sido implicada na patogênese da DPOC. Quimiocinas como CXCL9/MIG, CXCL10/IP-10, CXCL11/I-TAC e CCL5/RANTES têm sido descritas como possíveis responsáveis pelo recrutamento de linfócitos T e monócitos sanguíneos, facilitando o aumento de macrófagos alveolares e linfócitos T CD8+ no parênquima dos pacientes com DPOC. Conhecer melhor como ocorre o tráfego de células mononuclerares em direção ao pulmão é fundamental não só para um maior entendimento da patogênese da DPOC, mas para o desenvolvimento de terapêuticas adequadas. Com base nessas evidências tem sido proposto o estudo de moléculas capazes de bloquear de forma específica o recrutamento de células inflamatórias para o pulmão por meio de ação direta nos seus receptores.Unitermos: DPOC. Inflamação. Quimiocinas.células inflamatórias e seus mediadores na patogênese da dpoc

show abstract

Multifaceted mechanisms in COPD: inflammation, immunity, and tissue repair and destruction

Cited by 518 publications

References 304 publications

Local and systemic cellular inflammation and cytokine release in chronic obstructive pulmonary disease

Local and systemic cellular inflammation and cytokine release in chronic obstructive pulmonary disease

MicroRNA-223 controls the expression of histone deacetylase 2: a novel axis in COPD

Células inflamatórias e seus mediadores na patogênese da DPOC

Contact Info

Product

Resources

About