Hypoxia‐inducible factor and bacterial infections in chronic obstructive pulmonary disease

Abstract

COPD is a seriously disabling respiratory condition that inexorably progresses to disability and mortality. It affects approximately 10% of the population globally with a greater prevalence at advanced ages. Airway bacterial infections complicate the disease course in most COPD patients, leading to increased symptoms, more rapid decline in lung function, acute exacerbations and reduced quality of life. With increasing bacterial resistance to antibiotics and adverse effects of conventional treatments, new effective non‐antibiotic antimicrobial therapies are urgently needed to manage COPD. Hypoxia‐inducible factor (HIF)‐1α is an important transcriptional regulator of cellular responses to hypoxia, oxidants and inflammation, and is overexpressed in the lungs of COPD patients. Recent evidence shows that increased HIF‐1α expression can upregulate the platelet‐activating factor receptor (PAFR) on the airway epithelial surface that is increased in smokers and particularly COPD patients. The receptor is utilized by PAFR‐dependent bacteria (Streptococcus pneumoniae, Haemophilus influenzae and Pseudomonas aeruginosa) to induce infection in both the respiratory and gastrointestinal (GI) tracts. However, the importance and mechanism of HIF‐1α in augmenting PAFR‐dependent bacterial infections in COPD are poorly understood. Here, we review the evidence for the roles of local tissue hypoxia‐induced inflammation, HIF‐1α and PAFR in facilitating bacterial infections in COPD. Blocking PAFR may provide a novel antimicrobial approach to manage bacterial infections in COPD.

The sputum microbiome is distinct between COPD and health, independent of smoking history

“…Other pathological factors may therefore be important in shaping the microbiome in COPD. Hypoxia and chronic systemic inflammation related factors, which are features of COPD, have been reported to be associated with the airway microbiome [31] and may be relevant to the differences observed in our COPD cohort.…”

Impact of diet and the bacterial microbiome on the mucous barrier and immune disorders

“…Cigarette smoke exposure reduced anti‐inflammatory SCFA levels in caecum contents of rats 224 and induced mild colitis‐like changes in the gut which predisposes to chemically induced colitis in mice 54 . Conversely, chemically induced colitis induced IL‐6‐driven neutrophilic lung inflammation associated with presumably gut‐derived bacterial endotoxin 53 and increased platelet‐activating factor receptor that also drives inflammation and potentially predisposes to infection 225,226 . Cigarette smoke also increased colonic hypoxia and oxidative stress in mice 226 .…”

GPNMB contributes to a vicious circle for chronic obstructive pulmonary disease

“…When GPNMB was added to the set of 210 genes previously identified as involved in the pathogenesis of both OP and COPD, a total of 116 enriched pathways were detected (OP COPD→GSEA) (P<1e −25 ). Many of these pathways have obvious connection to both diseases, such as response to hypoxia, which affects the bone marrow stem cells differentiation in bone marrow cavity in osteoporotic patients [31] and induces oxidative stress, coagulation, inflammation, and angiogenesis in COPD [32].…”