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International Journal of Chronic Obstructive Pulmonary Disease Volume 14, 2019 - Issue
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Review

The etiologic origins for chronic obstructive pulmonary disease

Xinwei Huang1 Faculty of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming City, Yunnan Province, People’s Republic of China;2 Medical School, Kunming University of Science and Technology, Kunming City, Yunnan Province, People’s Republic of China
,
Xi Mu3 Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming City, Yunnan Province, People’s Republic of China
,
Li Deng4 The Pathology Department, First People‘s Hospital of Yunnan Province, Kunming City, Yunnan Province, People’s Republic of China
,
Aili Fu5 Department of Oncology, Yunfeng Hospital, Xuanwei City, Yunnan Province, People’s Republic of China
,
Endong Pu6 Department of Thoracic Surgery, Yunfeng Hospital, Xuanwei City, Yunnan Province, People’s Republic of China
,
Tao Tang2 Medical School, Kunming University of Science and Technology, Kunming City, Yunnan Province, People’s Republic of ChinaCorrespondence[email protected] [email protected]
&
Xiangyang Kong2 Medical School, Kunming University of Science and Technology, Kunming City, Yunnan Province, People’s Republic of ChinaCorrespondence[email protected] [email protected]
ORCID Iconhttps://orcid.org/0000-0001-8184-2493
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Pages 1139-1158 | Published online: 27 May 2019

Abstract

COPD, characterized by long-term poorly irreversible airway limitation and persistent respiratory symptoms, has resulted in enormous challenges to human health worldwide, with increasing rates of prevalence, death, and disability. Although its origin was thought to be in the interactions of genetic with environmental factors, the effects of environmental factors on the disease during different life stages remain little known. Without clear mechanisms and radical cure for it, early screening and prevention of COPD seem to be important. In this review, we will discuss the etiologic origins for poor lung function and COPD caused by specific adverse effects during corresponding life stages, as well as try to find new insights and potential prevention strategies for this disease.

Introduction

COPD, characterized by long-term poorly irreversible airway limitation and persistent respiratory symptoms, is a common and preventable disease.Citation1 According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, three criteria are needed to diagnose the disease: (1) a post-bronchodilator FEV1:FVC ratioof less than 70%, (2) “appropriate symptoms” such as dyspnea, sputum production, chronic cough, or wheezing, (3) “significant exposures to noxious environmental stimuli.Citation2 This disease has at least three phenotypes: emphysema, chronic bronchitis, and small airway remodeling and obstruction,Citation3 and environmental and genetic factors are involved in the pathogenesis and development of the disease. Cigarette smoking is main cause of the disease, whereas only 10–20% of smokers develop COPD,Citation4 and approximately 25–45% of occurrence of COPD is attributed to nonsmoking risk.Citation5 As shown in (The Global Burden of Disease study 2017),Citation6 COPD attributed to active smoking, ambient particulate matter pollution, occupational particulate matter/gases/fumes, ambient ozone pollution, household air pollution from solid fuels, secondhand smoke, and lead exposure was responsible for about 3.46 million of global all-age deaths and 79.78 million of disability-adjusted life-years (DALYs) in 2017. Active smoking and ambient particulate matter pollution were the main causes of deaths and DALYs for COPD (). Although the global age-standardized death rates and DALY rates for COPD attributing to each of the above risk factors between 2007 and 2017 was reduced, this epidemical tendency forecasting is not optimistic as the growth and aging of population. Nowadays COPD is the fourth leading cause of death worldwide and will become the third leading cause of death by 2030,Citation7 thus it will be an urgent health problem to be solved. Without curative therapies for COPD, palliation of airway obstruction, symptoms and exacerbation are the main clinical managements currently. Therefore, addressing the predisposing factors of COPD and prevent its development seemto be an appropriate intervention strategy for control of the disease in public health. Understanding the effects of risk factors correlated with the development of this disease on population at their different life stages is necessary so that more preventive strategies may be developed. In this review, we will provide a broad overview of etiologic origins for COPD, and try to find some potential preventive strategies and new insights for COPD studies.

Table 1 Global all-age attributable deaths and DALYs, and percentage change of age-standardized death rates and DALY rates caused of COPD by environment exposure between 2007 and 2017

Figure 1 The proportion of all-age deaths and DALYs for COPD attributed to active cigarette smoking, ambient particulate matter pollution, occupational particulate matter/gases/fumes, ambient ozone pollution, household air pollution from solid fuel, and secondhand smoke in 2007 and 2017.

Notes: This data comes from part of the article Stanaway JD, Afshin A, Gakidou E, et al. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1923–1994.Citation6 R 3.5.2 version was used to plot.

Abbreviation: DALYs, disability-adjusted life-years.
Figure 1 The proportion of all-age deaths and DALYs for COPD attributed to active cigarette smoking, ambient particulate matter pollution, occupational particulate matter/gases/fumes, ambient ozone pollution, household air pollution from solid fuel, and secondhand smoke in 2007 and 2017.Notes: This data comes from part of the article Stanaway JD, Afshin A, Gakidou E, et al. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1923–1994.Citation6 R 3.5.2 version was used to plot.

The genetic, epigenetic, and transcriptional origins of COPDand poor lung function

The genetic origins

COPD and poor lung function (FEV1, FEV1/FVC) may already be determined before the birth for some patients. COPD shows independent family aggregation,Citation8–Citation10 and COPD family history shows 18.6% of the population-attributable risk, with more severe diseases, worse quality of life, and more frequent exacerbations.Citation11 In addition, asthma with family aggregation is observed to be the indirect risk of COPD.Citation12 Similarly, inter-individual difference in lung function is partly defined by genetic reasons. The infants with the lowest quartile of functional residual capacity of the FEV1/FVC ratio and FEV1 were lower than that with the highest quartile up to age 22.Citation13 Heritability of FEV1/FVC was higher than that of either FEV1 or FVC, and a significant difference in lung function exists between males and females. Males have higher FEV1 and FVC, while females have higher FEV1/FVC.Citation14 The genome-wide association study (GWAS), whole genome sequencing (WGS), and fine-mapping studies have consistently discovered and well-replicated many COPD associated genes (COPD genes) and loci in various populations. As summarized in ,Citation15–Citation68 a panel of genes associated with COPD and poor lung function, nicotine addiction, and lung injury-repair response are indicated.

Table 2 Genes involved in COPD

The early abnormal lung development including airway and alveolar development might underlie the susceptibility to COPD and impaired lung function.Citation3 The normal expression of NKX2-1, the first symbol of lung development, plays a critical role in morphogenesis of the anterior foregut and the lung and in differentiation of lung epithelial cells.Citation26,Citation27 The mice lung with its heterozygous mutation failed to undergo normal branching embryogenesis and was unable to sustain normal gas exchange function, and subsequently causes immediate postnatal lethality.Citation26 The hedgehog (hh) pathway transmits signals to embryonic cells and is one of the key pathways of animal development.Citation69 The functional loss in HHIP may lead to impaired branching morphogenesis and lung hypoplasia in mice.Citation31,Citation38 Retinoic acid receptor-beta (RARB) plays a key role in septation mature and alveoli formation of mice lung. RARB knockout mice showed premature septation, and they formed alveoli two times faster than that of wild-type mice during the period of septation.Citation43 The transcription factor SOX5, a susceptibility gene for COPD, is critical for proper in utero lung morphogenesis. SOX5 deficiency mice exhibited delayed lung development before the saccular stage.Citation23 Another COPD gene TGFB2 involves cellular growth, differentiation, and apoptosis, as well as other cellular functions from development to tissue homeostasis, also plays an important role in normal lung development, airway remodeling, and the immune system.Citation28,Citation30–Citation35 The roles of matrix metalloproteinase (MMP) family and tissue inhibitors of MMPs (TIMPs), and CD147 in the lung development, lung repair responses to injury, and occurrence of multiple lung diseases including COPD and emphysema were well reviewed by Hendrix and Kheradmand.Citation44During lung development, MMP1/2/3/7/9/12/14/21, CD147, and TIMP1/2/3 play important roles. These genes have different expression levels in different cell types of the lung during different developmental stages.Citation70,Citation71 The lack of MMP14 in mice may decrease alveolar enlarged airspaces and surface area, as well as delay angiogenesis.Citation49,Citation50 In addition, CD147, MMP7, and MMP14 might be involved in lung injury-repair response.Citation46,Citation51–Citation53 ADAM33 also plays different roles in different developmental stages, including antenatal airway lung morphogenesis and airway wall modeling,Citation15,Citation16 and contributes to asthma and bronchial hyperresponsiveness in early life and in adults.Citation16,Citation21 The interaction of ADAM33 with prenatal smoking exposure could lead to reduced lung function and development of asthma at the age of 8.Citation22 Moreover, polymorphisms of this gene, especially in its functionally relevant 5′ end, were related to the preschool children with increased airway resistance and impaired lung function and COPD susceptibility.Citation20 Taken together, many GWAS-identified COPD genes play key roles in lung development and lung injury-repair response, and their abnormal expression modulated by variation or disturbance of maternal environmental exposure before the birth of individuals may pave the way for COPD development and poor lung function.

In addition, many COPD genes contribute to COPD development and poor lung function in childhood and adulthood of individuals through cross talking with environmental exposure factors. As shown in , many other COPD genes were showed to be associated with FEV1/FVC, FVC, and FEV1 of the population in different life stages. The polymorphisms at positions Arg16Gly/Gln27Glu within ADRB2 were found to be associated with airway responsiveness at the age of 6, with higher spirometry at the age of 6 and 11, as well as with the presence of COPD, asthma, and other respiratory symptoms in middle-aged and older adults,Citation61 whereas associated with worse lung function and less likelihood of the asthma diagnosis at the age of 11.Citation62 CC-16 was showed to accelerate decline in lung function in childhood and adulthood, as well as promotethe progress of moderate airflow limitation in adults.Citation65 A follow-up study on fetalbirths indicated that several detoxification genes including EPHX1, CYP1A1, and GSTT1, which are implicated in the development of emphysema and COPD, may modify the impact of cigarette smoke exposure and ambient air pollutants such as PM2.5 and polycyclic aromatic hydrocarbons (PAHs) on acute bronchitis in their later life.Citation72–Citation75 In some cases, nicotine addiction increases cigarette smoking, thus increases the COPD risk and impair lung function. Some genes associated with nicotine addiction were reviewed, including CHRNA3/4/5/7, DRD4, SLC6A3, SLC6A4, NRXN1, HTR2A, CHRNA7, CYP2A6,Citation47 of which, HTR2A, CYP2A6, and CHRNA3/4/5/7 are involved in COPD pathogenesis depending partly on cigarette exposure due to a gene-by-environment interaction.Citation54,Citation55–Citation57 HTR2A may increase the risk for the early onset of cigarette smoking and the risk for relapsing after smoking cessation.Citation55 Furthermore, the gene cluster of CHRNA3/CHRNA5/CHRNB4 plays an important role in the cigarette smoke-causing injury process. Smoking behavior may mediate the relationship between COPD and the rs1051730 mapped to CHRNA3/5.Citation76 However, the mechanism of CHRNA3/5 increasing the respiratory diseases risk is controversial: either CHRNA3/5 has an independent effect or the regulation of nicotine addiction on COPD development.Citation77,Citation78

Epigenetic origins

During the lung development, some epigenetic alterations including: DNA methylation, histone modifications, and noncoding RNAs are key regulators of the process. An individual’s epigenetic alterations of genes that may originate from his parents or grandparents could subsequently persist well into childhood.Citation79–Citation81 Developmental programming, occurring primarily via epigenetic alterations, can be induced by the intrauterine conditions such as cigarette smoking, nutrition and stress, and result in inter- and transgenerational epigenetic effects on genetic origins in mice and their offspring.Citation82,Citation83 Reprogramming of the epigenome, genetic imprinting, retained nucleosomes may be the potential mechanism of inter- and transgenerational epigenetic effects.Citation82 Epidemiological and experimental evidence indicated that exposure to environmental factors during prenatal and early postnatal period upon the epigenome is critical in embryonic development and tissue differentiation may lead to permanent epigenetic modifications and contribute to the possibility of developing adult-onset disorders such as metabolic, cardiovascular, lung cancer, lung function, and COPD.Citation79,Citation82,Citation84,Citation85 Epigenetic regulation is important in chronic remodeling of respiratory tracts.Citation86 DNA methylation is an established mechanism for COPD development,Citation87 which may be regulated by genetic polymorphisms.Citation82,Citation88 As the key regulators of lung development, histones are usually modified by methylation, phosphorylation, acetylation, and ubiquitination of specific amino acids. Especially, histone acetylation is crucial in regulation of lung development and function, and is implicated with asthma and COPD.Citation89–Citation91 Histone acetyltransferases (HATs) mediates histone acetylation that increases gene expression, whereas histone deacetylases (HDACs) induces hypocetylation that promotes gene silencing.Citation89 Thus, the imbalance between HATs and HDACs activity caused by any adverse factors may lead to disorders of embryonic lung development, including the block in proximal airway development,Citation92 alveolar hyperplasia,Citation93 and disrupted alveolarization.Citation94 In addition, the methyltransferases Suv39H1 and Suv39H2 that result in transcriptional silencing through histone H3 lysine 9 methylationare are involved in all lung development processes.Citation95 Thus, the disturbance of necessary epigenetic alterations resulting from genetic variation or adverse risk factors during the prenatal and early postnatal period may influence the lung development of the fetus.

Postnatal environmental factors including cigarette smoking, aging and diet, as well as genetic risk factors such as genetic variation, can modulate the methylation modification of promoter CpG via DNA methyltransferases and methyl CpG binding protein 2, which affects the transcription and expression/activation of some key genes involved in pathogenesis of COPD and impaired lung function.Citation96–Citation98 Different risk factors can induce distinctive DNA methylation profiling on genome of individuals including patients with COPD and healthy people.Citation98–Citation100 Methylation at cg08257009 in the SERPINA gene cluster was found to be associated with FEV1/FVC in adults.Citation101 Furthermore, one epigenome-wide association analysis (EWAS) in whole blood found that methylation at 15 CpG-sites was significantly associated with cigarette smoking and lung function, of which, 5 methylated CpG-sites (cg05575921, cg21161138, cg05951221, cg21566642, and cg06126421) showed significant associations between DNA methylation and gene expression in lung tissues.Citation102 Another EWAS of four SNP (rs8034191:T>C-HYKK, rs12914385:C>T-CHRNA3, rs13180: C>T-IREB2 and rs8042238:C>T-IREB2), previously related to COPD, showed a significant association with blood DNA methylation of those genes, of which, PSMA4 and IREB2 were also differentially methylated in COPD cases and controls. In addition, all four variants also showed a significant correlation with differential expression of the IREB2 3ʹUTR in lung tissues.Citation103

Taken together, genetic and environmental factors, and their cross talking may influence the early lung development, and result in COPD and poor lung function later via epigenetic modifications that modulate thiss activation and transcription of COPD genes.

MicroRNAs origins

The increasing human/animal models and cell studies demonstrated that microRNAs (miRNAs) play a central regulatory role in various biological processes, including cellular proliferation, differentiation and apoptosis. MiRNAs play key roles in the lung development, and pulmonary diseases such as COPD, whereas the degree of translation into pulmonary diseases is still unclear. Recently, we reviewed the roles of miRNAs in COPD development induced by different environmental exposure as well as genetic predisposition encounter. Environmental exposure including air pollutants and cigarette smoking can induce dysregulated miRNA expression profiles, which cause adverse biological response such as oxidative stress, inflammation, and the imbalance between apoptosis and replenishment of structural cells in the lung by disturbing their regulation on COPD genes, and contribute to COPD development and poor lung function in susceptible individuals. In addition, functional SNP variant with miRNA genes can affect the mature form of corresponding miRNAs and disturb the regulation of them on COPD genes, thus leading to COPD susceptibility. Some key miRNAs, such as miR-34 a/b/c, miR-146a, miR-203, miR-218 and let-7 family, may serve as potential fluid biopsy-based markers for risk indicators of environmental exposure and COPD.Citation104

The environmental origins of COPDand poor lung function

Although without absolute consistence with the pulmonary development phase division, it is traditionally divided into five histological stages from the embryonic stage to the alveolar stage ().Citation105,Citation106 Two follow-up studies conducted on participants aged from 13 to 71 years showed that the plateau of FEV1 is 20–23 years old for males, and 15 for females, whereas the decline in FEV1 occurs at about 25 years old for both sexes, suggesting a longer plateau phase for FEV1 in females than in males.Citation107,Citation108 Moreover, the FEV1/FVC ratio increased until 17 years old in males and then declines approximately linearly, whereas this ratio indicated a uniform decline in the age range in females.Citation107,Citation108 Interestingly, although cigarette smoking can increase the rate of lung function decline in both sexes, it can only reduce the achieved peak of FEV1 value in males, but not in females.Citation108  Those observations suggest a congenital difference of lung function among sexes. The difference may originate from hereditary difference from the gender-biased environmental exposure ways between males and females.

Table 3 The different risk factors during varied life periods of the lung

Another follow-up study showed that the antenatal adverse factors and early childhood disadvantage factors lead to permanent lung function impairment, with a slightly greater decline in lung function but no catching up with age.Citation109 COPD risk increases with increasing early-life adverse factors, of which, the impacts resulting from childhood asthma, maternal and paternal asthma, maternal smoking, and respiratory infections are the same as strongly implicated in an accelerated decline rate of lung function as that of severe smoking. The tendency of decline in lung function increased with the accumulative degree of smoking exposure (healthy never smokers, quitting smoking before the age of 30, quitting smoking between 30 and 40 years, quitting smoking after the age of 40, continuous smokers),Citation107 suggesting that the different degrees of exposure to environmental factors might lead to different degrees of lung function impairment.

Maternal amniotic fluid

Maternal amniotic fluid has important impacts on fetal lung development and respiratory disease occurrence in offspring. Oligohydramnios can lead to fetal lung hypoplasia, while the extent depends on the degree and duration of little amniotic fluid, and the fetal lung development stages.Citation110,Citation111 Fetal lung development may be regulated by amniotic fluid components such as pro-inflammatory mediators.Citation112 Plasminogen activator inhibitor 1 (PAI-1) is a main inhibitor of the fibrinolytic system and plays an important role in tissue remodeling,Citation113 and its reduction is associated with cough at 1 year of age and wheeze at 2 years of age.Citation114

Preterm birth and birth weight gain

Preterm birth is the main risk for bronchopulmonary dysplasia (BPD) that accounts for the prevalence of the vast majority of chronic pulmonary diseasesCitation115,Citation116 and is a risk factor of permanent lung function decline.Citation117–Citation120 Preterm birth is also associated with school-age and adult asthma,Citation112,Citation118 wheeze and breath shortness,Citation121 COPD,Citation122 as well as bronchial hyperresponsiveness and decreased FEV1.Citation120

In addition, low birth weight may lead to persistent decline in lung function and different degree of airway obstruction, and increase risk of respiratory symptoms.Citation123–Citation125 Interestingly, a meta-analysis report of 147,000 European children observed an independent relationship between higher infant weight gain and the higher risk of school-age asthma and preschool wheezing.Citation112 The mechanism between birth weight and COPD needs further study.

Maternal cigarette smoking

Antenatal adverse exposure may lead to the lung’s response, making it more predisposed to subsequent injury.Citation116 Fetal exposure to maternal smoking during pregnancy is one of the most serious events for abnormal lung development,Citation126 it can increase the risk of poor lung function, COPD, asthma, and childhood wheeze.Citation122,Citation127–Citation130 The mechanisms might partly result from epigenetic alterations because of the global DNA methylation in umbilical-cord blood was observed to be associated with prenatal exposure to PAH,Citation131 which is the main harmful component of incomplete combustion of cigarettes.

Maternal air pollution exposure

Preconceptional and prenatal exposure to industrial and traffic air pollutants increases risk of childhood asthma, allergic rhinitis, and eczema.Citation132 Particulate matter smaller than 2.5 µm (PM2.5), composed of ammonium, nitrate and bromine, mainly results from traffic and biomass combustion.Citation133 Maternal sulfur dioxide (SO2) and PM2.5 exposure were found to be associated with preterm birth and low birth weight, and childhood asthma.Citation133–Citation135 Residential PM2.5 exposure was showed to influence the expression of placental imprinted genes, suggesting a plausible line of investigation of how air pollution affects fetal growth and development.Citation136 Maternal PM10 exposure was reported to increase the risk of congenital anomaly, notably fetal growth and development, and is related to placental DNA methylation, such as the LINE1 and HSD11B2 genes.Citation137 In the pilot study of 44 mother-infant pairs, Kingsley et alCitation138 observed an association of prenatal perfluorooctanoic acid exposure with cord blood leukocyte DNA methylation in two CpG sites of RASA3 that plays a key role in cell growth and differentiation.Citation139

Delivery patterns

Delivery mode shapes individual microbiota’s acquisition and establishment, which may influence children’s health.Citation140 Maternal vaginal microbiota provides a natural first-class microbial exposure resembling the mother’s vaginal microbiota’s habitat on infant’s body via natural labor. Whereas cesarean section that lacks a vaginal exposure leads to the first microbial community resembling the maternal skin microbiota.Citation140 Furthermore, cesarean section could increase the risk of allergic rhinitis, asthma, and hospitalization for asthma.Citation141 These suggest that delivery patterns may lead to difference in normal physiology or contribute to respiratory diseases due to variations in the microbiota development. Previous studies commonly focused on the specific bacterial taxa of the gut, however, the role of respiratory tract flora in pulmonary disease occurrence is little known.

Maternal obesity

The role of maternal obesity in their children has been reviewed by Duijts et al.Citation142 Pre-pregnancy obesity, and higher gestational weight gain and maternal overweight or obesity during pregnancy is associated with the higher risk of respiratory diseases, such as wheezing and asthma in their offspring.Citation143,Citation144,Citation145 Thus, maternal obesity may be a risk of COPD, but further investigation is still needed.

Maternal diet and drug use

Maternal diet or drug use during pregnancy may regulate the risk of respiratory diseases in offspring, which may be caused by the interactions between maternal nutrition intake and genetic alterations, as well as by immune regulation, epigenetic modifications, and microbial changes. The overfull folic acid and free sugars intake in pregnant women were shown to increase the risk of asthma in offspring,Citation146,Citation147 which may be due to the role of the nutrition in airway inflammation and hyperreactivity in late generations.Citation148 Hypercaloric diet (HFD) of pregnant dams could lead to metabolic abnormalities that may persist throughout development,Citation148 and inflammatory response in the pups’ lungs.Citation149 The intake of HFD + antioxidant N-acetylcysteine (NAC) in pregnant dams was showed to delay the alveolarization of pups, although their branching morphogenesis is normal.Citation150 While maternal intake of some vitamins, microelements, and folic acid was found to have protective effects on some respiratory diseases in offspringCitation151 and may modulate epigenetic modifications on gene expression and airway epithelial cell signaling in fetal lung, which may affect intrauterine programming of growth and development.Citation152,Citation153 Polymorphisms within some genes involve the regulation of maternal antioxidant intake on offspring respiratory disease.Citation154 Furthermore, intrauterine antibiotic exposure plays important roles in the health of offspring through interfering with normal metabolic and immune maturation,Citation155 affecting the fetal organogenesis and development by methylation alterations and placental microbiome changes.Citation156,Citation157 Prenatal cocaine exposure in the placenta might affect neurochemical effects, vasoconstrictive, and fetal programming. Maternal diet and drug use during pregnancy are an increasing focused topic, because they are modifiable causes of disease in offspring. However, these complex links and mechanisms between maternal intake and COPD are necessary to reveal.

Childhood air pollution exposure

Early life air pollution exposure including traffic-derived CO, NO, NO2, PM2.5, PM10, SO2, and black carbon appears to influence the development of airway diseases and increase risk of respiratory diseases, including COPD and asthma in later life.Citation158–Citation161 A prospective birth cohort study during the first 6 years of life indicated that early childhood air pollution exposure to PM2.5 increased the risk of early respiratory diseases,Citation162 which was similar to another prospective study observation in children of Sweden.Citation163 PM2.5 can induce both chemical and physical damage by penetrating the alveoli into the systemic circulation, whereas PM10 usually causes physical damage to the lungs, such as the alveoli and larynx.Citation164 As we known, at least three mechanisms are thought to be involved in the causal processes: occurrence of oxidative stress, inflammation, and epigenetic alterations. Firstly, PM-induced excessive ROScauses oxidative stress that leads to cell function impairment and cell death.Citation165 Secondly, oxidative stress alters the expression of proteins related to inflammatory response in the airways.Citation166 Additionally, PM may induce epigenetic changes including aberrant DNA methylation and histone modifications of key genes like LINE-1, IL-8 and COX-2, and influence the inflammatory response.Citation167–Citation169

Childhood asthma

Childhood asthma is an established risk factor for low lung function and predisposition to COPD in adult.Citation109,Citation170–Citation176 Although the clear mechanism between COPD development stemming from childhood asthma history is poorly understood, the overlapped genetic variations between COPD and asthma were identified by previous GWAS.Citation172,Citation177 Interestingly, Bui et al performed a cohort study in Tasmanian children (N=8,583) aged 7–45 years and found that the lowest quartile of FEV1 at 7 years old in a selected subsample (N=1,389) was related to asthma-COPD overlap syndrome (ACOS) but not asthma or COPD alone, and observed the association of the lowest quartile of FEV1/FVC ratio at 7 years with COPD (OR: 5.76; 95%CI: 1.9–17.4) and ACOS (OR: 16.3; 95%CI: 4.7–55.9), but not with asthma alone,Citation172 suggesting that screening for lung function in children may provide help in identifying the high-risk group of COPD. Interestingly, the assessment of airway hyperresponsiveness that correlates with airway inflammation, asthma, and remodelling may contribute to estimate of asthma control and future exacerbation risk, although this procedure is still a study tool for asthma.Citation178,Citation179

Childhood respiratory infection

Normal respiratory tract microbiome is important in immunological development and allergic inflammatory response, which modulates the COPD risk.Citation180,Citation181 Childhood respiratory infection was demonstrated to be associated with lower lung function and increased COPD risk in later life.Citation122,Citation182,Citation183 Early respiratory infection including virus and bacterial flora is predominantly related to a series of respiratory diseases. Viral respiratory tract infections especially respiratory syncytial virus (RSV) and human rhinovirus (HRV) in infancy and early childhood may promote the risk of asthma and wheezing later.Citation184,Citation185 Children with a history of HRV infection could contribute to the occurrence of asthma in preschool age.Citation186 Children who suffer from RSV-bronchiolitis could increase the risk of lower lung function, asthma, wheezing, hospitalization and respiratory morbidity in later life.Citation186–Citation189 Even though the mechanisms between respiratory diseases and infection are poorly known, it may at least partly result from genetic factors. Some variants of the 17q21 locus were observed to be implicated in childhood asthma, and also associated with early-life infection and HRV-induced wheezing.Citation183,Citation190 Protecting children from being “at risk” during infancy or early childhood is a way to prevent serious respiratory infection, meaning an effectively preventive strategy for respiratory diseases.

Childhood cigarette smoking exposure

Early childhood smoking exposure majorly comes from parental secondary smoking with less active smoking. Early family cigarette smoking exposure can easily impair lung function and increase the later risk of respiratory diseases in children.Citation191 Previous prospective cohort studies indicated that childhood cigarette smoking exposure from families leaded to reduced lung function, active smoking predisposition, airway obstruction susceptibility and early onset COPD, as well as prevalence of bronchodilator responsiveness, asthma and wheeze in later life.Citation192–Citation194 Parental smoking cessation and public-place banning cigarette smoke may be an effective measure for prevention of children’s respiratory diseases and COPD occurrence in later life.

Childhood obesity/nutritional factors

Obesity is not only prevalent among adults but also occurs in children.Citation195 Childhood obesity is an increased risk of chronic respiratory diseases. Asthma is consistently one of the most common diseases among children. Presently, the relationship between childhood obesity and COPD are still largely unknown, but some evidence about the effects of childhood obesity on early asthma and airflow obstruction was found.Citation112,Citation196–Citation200 The leukotriene pathway and some overlapping genes between obesity and asthma including β2-adrenergic receptor (ADRB2), TNF-a, lymphotoxin-a (LTA), vitamin D receptor (VDR),Citation201 and protein kinase C alpha (PAKCA)Citation202 were demonstrated to play important roles in the obesity-asthma phenotype.Citation197 Additionally, age is a significant effect modifier of obesity and asthma. As asthma increases, the impact of obesity on asthma may decrease.Citation197 The etiologies for COPD and asthma caused by obesity partly root in obesity-induced circulating inflammation in the lung, and airway smooth muscle dysfunction.Citation197,Citation203–Citation207

Nutritional factors may play an important role in the development, progression and administration of pulmonary diseases such as COPD and asthma.Citation208 High-fat diet pattern was shown to be associated with increased risk of childhood asthma and COPD,Citation209,Citation210 likely by augmenting neutrophil airway inflammation and suppressing bronchodilator’s recovery.Citation211 Furthermore, eating fast food is correlated with the prevalence of asthma, airway hyperresponsiveness, and wheezing in childhood.Citation212,Citation213 Some antioxidants in lungs including uric acid, vitamins C and E, glutathione and beta-carotene are the first line of defending against the oxidants to increase risk of COPD, idiopathic pulmonary fibrosis and asthma.Citation214 Abnormal concentration of these antioxidants may increase risk of lower lung function, current wheezing, and asthma.Citation215,Citation216 This may be explained by several potential biological mechanisms, including impaired pathogen elimination of respiratory airways,Citation217 abnormal regulation of Th17 cells,Citation218 as well as reduced maturation of airway smooth muscle cells and suppressor T cells.Citation197 Modifying dietary fat intake and reducing obesity may be helpful to control and manage asthma and COPD.

Adulthood cigarette smoking exposure

Cigarette smoking and secondhand smoke exposure in adulthood contributes to the development of COPD and the increasing mortality of COPD, although persist smoking cessation.Citation191,Citation210,Citation219 The excess risk of developing COPD in high cigarette smoke exposure categories was estimated 60–400%.Citation220 Whilethere is controversy between smoking predisposition and gender,. one study showed that females have a higher susceptibility to cigarette smoking, another reported the same level of predisposition for both sexes.Citation219,Citation221 The burden of COPD would increase in women as cigarette smoking prevalence increased, and as young women started smoking at an earlier agecigarette smoking.Citation161 The main causative processes at least involve oxidants-antioxidants, proteases-antiproteases, improper repair, and chronic inflammation of airways.Citation219 These processes result in alveolar wall destruction and mucus hypersecretion, functional disorder and death of biomolecules, destruction of extracellular matrix, and fibrosis of lung with submucosal, adventitial and smooth muscle thickening.Citation219 Therefore, inhibiting the pathogenesis of COPD should be a good strategy for the treatment and symptom improvement of the disease. Quitting smoking early is of great benefit in COPD development and the decline in lung function, especially before the age of 30 when the rate of lung function decline in those who had quitsmoking is indistinguishable from healthy nonsmokers.Citation107

Adulthood air pollution exposure

Approximately 50% of all households and 90% of rural households use biomass fuel for heating and cooking, which accounts for over three billion people exposed to biomass smoke.Citation160,Citation222 Even in modern homes in some developed countries, biomass fuel is unable to be replaced by the ever-increasing cost of clean fuels.Citation223 Women seem to suffer from more biomass smoke exposure because they could inhale over 25 million liters of highly polluted air during their lifetime when they spend an average of 60,000 hours cooking near a biomass stove.Citation224 Biomass fuel including fossil coal, animal dung, wood and crop residues has low efficiency due to less heat production and incomplete burning, and releases more than 200 established chemical compounds, including gaseous and particulate pollutants and strong oxidant properties. Over 90% of those chemical compounds could penetrate deep into the lungs and result in chronic inflammation and destructive changes in airways and alveoli.Citation160,Citation224

Compared with no exposure to biomass smoke, exposure to biomass fuel smoke was observed to be associated with 2.44-fold and 2.4-fold increased odds of COPD in both sexes and women, respectively.Citation225,Citation226 Exposure to biomass smoke may be a greater risk factor for COPD compared with cigarette smoking exposure from a global perspective because of the number of people exposed to biomass smoke is three times more than smokers.Citation224,Citation227 COPD patients exposed to biomass smoke share part similar profile of cell and airway inflammation with smokers.Citation228 Compared with control women cooking with clean fuels, women cooking with biomass have more severe airway inflammation and oxidative stress when evaluated with the induced sputum.Citation229 The ventilation improvement has been demonstrated to be effective in reducing indoor biomass smoke,Citation230 which might decrease the burden of COPD.

Outdoor air pollution is mainly caused bymotor vehicle and industrial emissions and is related to various respiratory impairments, particularly in children aged 10–18 yearsCitation231 and women.Citation232 The heavier traffic density was shown to be associated with the greater declines in lung function.Citation232 Long-term exposure to ambient PM2.5 is associated with the decline in lung functionand increases risk of COPD.Citation233,Citation234 In addition, the COPD risk increases with the increase of PM10 levels,Citation235 whereas the prevalence of COPD and respiratory symptoms reduces with the decline in levels of PM10.Citation236 A population-based cohort study in Metropolitan Vancouver, Canada, reported that black carbon is responsible for the increase of COPD hospitalization and mortality, while wood smoke exposures increases the risk of COPD hospitalization.Citation237 The oxidative stress, hyperresponsiveness, inflammation, impaired cilia activity and amplification of viral infections in airways may explain the adverse effects of ambient air pollutants.Citation238

Occupational exposure

Occupational exposure, such as gases/fumes, biomass smoke, dust exposure, animal and crop planting, chemical exposure, is strongly associated with COPD.Citation98,Citation233,Citation239,Citation240 The recent National Health and Nutrition Examination Survey for the non-institutionalized civilian US indicated that prevalence of airflow obstruction varies by occupation and industry, and that mining, construction, manufacturing, prepress, bookbinders, installers, and repairers may influence airflow obstruction.Citation241 In addition, occupational exposure to gas, vapor, dust, or fumes was shown to be associated with COPD, airflow limitation, and emphysema.Citation242,Citation243 Compared to developed countries, occupational exposure is more serious in developing countries due to lack of adequate protection and lack of strict regulations in the workplace.Citation160 Therefore there would be a larger burden of COPD attributed to occupational exposure in developing countries compared to developed countries.

Conclusions

COPD is a heterogeneous and multifactorial disease. As shown in , COPD induced by active smoking, ambient particulate matter pollution, occupational particulate matter/gases/fumes, ambient ozone pollution, household air pollution from solid fuels, secondhand smoke, and lead exposure was responsible for about 3.46 million of global all-age deaths and 79.78 million of disability-adjusted life-years (DALYs) in 2017. Active smoking and ambient particulate matter pollution were the main causes of deaths and DALYs for COPD (). The status of death and DALY for COPD is getting worse withpopulation growth and aging. Therefore, COPD emerges as an enormous challenge to global health.

Individuals may suffer special exposure factors during different life stages (). In turn, these special factors could exhibit their own effects at different life stages. As summarized in and , host family history of respiratory diseases such as COPD, asthma, and emphysema, which may share some overlapping predisposing genes, is an established risk factor for COPD development and poor lung function. Some COPD genes such as ADAM33, SOX5, TNS1, SERPINE2, NKX2-1, TGFB2, HHIP, PTCH1, CELSR1, RARB, CD147, MMP1/2/3/7/9/12/14, and TIMP1/2/3 are critical for lung development (organogenesis, alveolarization, branching morphogenesis, and angiogenesis) or/and lung repair responses to injury (airway inflammation, oxidative stress, impaired cilia activity, and amplification). Whereas, some COPD genes, including HTR2A, CYP2A6, CHRNA3/4/5/7, and AGPHD1, are involved in nicotine addiction and toxicant metabolism. Environmental exposure such as cigarette smoking, biomass smoke, and indoor/outdoor air pollutant during all life stages of an individual has well-documented adverse effects on the lung development, lung function, and COPD susceptibility through cross talking with COPD genes by which environmental exposure pollutants might induce abnormal epigenetic modifications on genome and dysregulated miRNA expression profiles, disturbing the expression and function of COPD genes. Based on the previous findings, we may get an inference that adverse exposure during the different life stages might cause permanent impact on the lung, such as failure to reach the normal spirometric plateau, and the accumulative impairment in the lung that paves the way for COPD development. Lung function apparently reduces with more risk factors ().

Figure 2 The origins for chronic pulmonary disease resulting from genetic and environmental factors.

Figure 2 The origins for chronic pulmonary disease resulting from genetic and environmental factors.

Figure 3 The plausible trajectories to lung function by varied risk factors in different life stages of the lung.

Figure 3 The plausible trajectories to lung function by varied risk factors in different life stages of the lung.

COPD is common and preventable. Undoubtedly, avoidance of exposure to any adverse environmental factor would be advisable for individuals with/without COPD susceptibility. Preschool age is likely to be the key period for prevention of lung function and respiratory diseases, and measures starting in adulthood may be too late. Early childhood lung function screening, banning cigarette smoking in public places, respiratory infection prevention, searching biomarkers for evaluation of environmental exposure could be the effective protective measures against lung function impairment and COPD development. Interestingly, two oxidative damage-related produce such as 8-Oxo-2′-deoxyguanosine (8-OHdG) and LINE-1 may become epigenetic biomarkers induced by ROS generation resulting from environmental exposure.Citation167,Citation244,Citation245

In the future, investigation of genomics, epigenomics and transcriptomics for COPD development will remain urgent. Extensive studies on the diversity of structure and function for miRNAs associated with COPD development will give better insights into the selection of appropriate miRNAs serving as prognostic or therapeutic biomarkers for COPD. Notably, a technique that may safely remove DNA methylation, resulting in the direct re-installation of unmodified deoxycytidine (dC) from 5-formyl-deoxycytidine (fdC) undergoing C-C bond cleavage, has a potential to treat and prevent COPD caused by DNA methylation.Citation246 Furthermore, gene editing in bronchioalveolar stem cells (BASCs) and basal stem cells (BSCs) that might regenerate both trachea cilia and secrete epithelium and generate alveolar epithelium after extreme injury may contribute to the recovery from both alveolar and bronchiolar injury.Citation247–Citation251

Authors contributions

All authors contributed toward data analysis, drafting and critically revising the paper and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

Acknowledgments

This work was funded by the National Natural Science Foundation of China (81460007) and the Fund for Applied Basic Research in Yunnan Province, China (2013FZ182).

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