American Journal of Respiratory and Critical Care Medicine

Accelerated aging and smoking are driving forces for chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF); however, the clinical and pathological phenotypes are radically different. COPD involves the alveolar and airway compartments and is characterized by chronic inflammation and defective tissue repair, resulting in airway disease and emphysema. These processes lead to irreversible chronic airflow limitation. Interestingly, in COPD, the changes in the extracellular matrix in airways and lung parenchyma differ. In primarily small airways, it is characterized by a fibrotic process, with increased collagen and narrowed lumina (1). By contrast, the changes in the lung parenchyma are characterized by the net destruction of the alveolar walls with “vanishing” of the gas-exchanging surface without obvious fibrosis (2).

IPF is a chronic and progressive fibrosing interstitial pneumonia of unknown etiology driven by aberrantly activated epithelial cells (3, 4). The histopathological pattern is characterized by temporal and spatial heterogeneity with areas of normal-appearing lung parenchyma in close proximity to fibrotic areas with honeycombing, resulting in a marked increase of lung stiffness. Therefore, whereas emphysema is characterized by destruction of the interstitial framework and formation of “emphysematous spaces” resulting in increased lung volumes, in IPF, scarring and decreased lung volume are conspicuous features.

Despite these differences, COPD and IPF share a number of lung aging biopathological processes, smoking injuries, and even several convergent molecular pathways. The question, then, is why does an older smoking individual develop IPF instead of the much more common COPD?

Accelerated Aging Processes

Several aging-associated alterations are implicated in the development of IPF and COPD. For example, aberrant shortening of telomeres has been identified in alveolar epithelial cells in both diseases (5, 6), and telomerase mutations are a risk factor for familial IPF and for human emphysema in smokers with COPD (7).

Experimental models support these observations. Mice with short telomeres chronically exposed to cigarette smoke develop emphysematous lesions (8). Similarly, severe telomere dysfunction, with a high burden of telomere-induced DNA damage, is sufficient for the development of pulmonary fibrosis, whereas less severe shortening of telomeres requires additional damage in order for full-blown pulmonary fibrosis to develop (9).

Mitochondrial dysfunction and oxidative damage are critical mechanisms associated with aging, and both occur in IPF and COPD. Long-term exposure to cigarette smoke induces persistent changes in mitochondrial structure and function in human bronchial epithelial cells in vitro, and similar mitochondrial changes are present in bronchial epithelium from patients with severe COPD (10). Likewise, epithelial cells from IPF lungs show accumulation of dysmorphic and dysfunctional mitochondria with marked impairment in mitophagy (11). Consistent with these findings, oxidation induced by the excessive generation of mitochondrial reactive oxygen species plays an important role in the pathogenesis and progression of IPF and COPD (10, 1214).

DNA damage, telomere shortening, and high concentrations of reactive oxygen species are major causes of cell senescence, an important aging-associated process. Senescence is characterized by permanent cell cycle arrest and a complex secretory phenotype known as the senescence-associated secretory phenotype, which has a profound impact in the tissue microenvironment contributing to the physiological and pathological effects of this process (15). In this context, alveolar epithelial and fibroblast senescence are frequently found in IPF and COPD (1619). In IPF, senescent epithelial cells likely produce some of the numerous profibrotic mediators that characterize this disease. Similarly, senescent fibroblasts are resistant to apoptosis and produce increased concentrations of extracellular matrix components (15). In COPD, senescent fibroblasts and epithelial cells may contribute to the imbalances of inflammatory and repair processes, leading to structural changes in both the peripheral airways and the lung parenchyma (20).

Immunosenescence represents the progressive impairment of the immune system during aging affecting the immune responses to new antigens, increasing susceptibility to infection and the development of autoimmunity. Several similar features of immunosenescence, including an exaggerated loss of the costimulatory molecule CD28, have been described in COPD and IPF (21, 22).

Finally, in-depth profiling of the core lung transcriptome has demonstrated a number of convergent transcriptional regulatory hubs between IPF and COPD (23). Analysis of the transcriptional signatures of IPF and emphysema revealed shared processes, including the p53 pathway and the hypoxia pathway; this may mirror the response to the impaired gas exchange that occurs in both diseases. Moreover, both diseases share some common transcriptional regulatory motifs, with several of the same microRNAs (miRNAs) being included in the regulatory networks.

Numerous studies revealed profound genetic, epigenetic, and mechanistic differences between IPF and COPD (Figures 1A and 1B). In addition, the airway epithelium is the primary site of the earliest pathological changes in COPD initiating an inflammation-driven disease, whereas the alveolar epithelium is the primary target in IPF, originating an epithelium-driven disease (24, 25).

Genetic Architecture

Genome-wide association studies (GWASs) have revealed complex and different combinations of gene variants that increase the risk of developing IPF or COPD. In sporadic IPF, strong evidence has demonstrated that the MUC5B risk variant (rs35705950), located in the promoter region, remarkably increases the risk of developing this disease (26). In the largest case–control GWAS performed so far, several new risk alleles were identified (27). Among these, two common variants were in the TERT gene and another was near the TERC gene. Other variants included two SNPs in the DSP (desmoplakin) gene, two in the DPP9 (dipeptidyl-peptidase 9) gene, three in the OBFC1 (oligonucleotide-binding fold containing 1) gene, and one in the ATP11A (ATPase, class VI, type 11A) gene. These findings support the notion that common variants of genes involved in telomere biology, epithelial integrity, and host defense increase the susceptibility to develop sporadic IPF. Recently, a case–control exome-wide collapsing analysis revealed that (ultra)rare variants in TERT, RTEL1, and PARN, three telomere-related genes previously implicated in familial IPF, contributed to more than 10% of sporadic IPF. This finding further reinforces the concept that telomere dysfunction is involved in IPF pathogenesis (28).

In sharp contrast, a completely different set of gene variants has been identified in COPD, including, among others, HHIP (hedgehog-interacting protein), CHRNA5/3 (cholinergic receptor nicotinic α), HTR4 (5-hydroxytryptamine receptor 4), RIN3 (Ras and Rab interactor 3), TGFB2 (transforming growth factor-β2), CYP2A6 (cytochrome P450 family 2 subfamily A member 6), and IL-27 (29, 30). More recently, 26 combined cohorts comprising 15,256 COPD cases and 47,936 control subjects were examined (31). This analysis replicated 79 loci strongly associated with the disease in 9,498 COPD cases and 9,748 control subjects. The study corroborated most of the variants previously reported. Of note, four variants (DSP [two variants], FAM13A [family with sequence similarity 13 member A], and MAPT [microtubule-associated protein tau]) have also been associated with pulmonary fibrosis (27). Remarkably, for all these variants, the risk allele for fibrosis was protective against the development of COPD. Regarding pathways, risk gene variants in COPD are related to nicotine signaling and metabolism, serotonin signaling, and surfactant metabolism, among others, and strongly differ from the risk genetic architecture of IPF.

Developmental Pathways

Dysregulation of developmental pathways is increasingly being recognized in IPF and COPD, but following different directions.


The WNT (Wingless/integrase-1) family of secreted glycoproteins is involved in numerous processes of mammalian development, physiology, and pathophysiology. Recent evidence in COPD indicates that canonical WNT/β-catenin signaling is attenuated in the lung epithelium of emphysematous lungs affecting airway and alveolar repair during the development of the disease (32). Interestingly, a canonical-to-noncanonical WNT signaling shift has been identified in COPD lungs, leading to impaired alveolar epithelial cell repair (33). Specifically, decreased canonical WNT signaling affects the migration of alveolar epithelial cells, as well as their differentiation of type II to type I (AEC2 to AEC1, respectively) that is dependent on autocrine WNT/β-catenin signaling (34). In addition, it results in the impaired expression of the transcription factor Nkx2.1, which closely correlates to the expression of the canonical WNT target gene AXIN2 in individuals with and without COPD (34). This transcription factor transactivates promoters of surfactant proteins and is essential for lung morphogenesis. Moreover, preventive and therapeutic activation of the Wnt/β-catenin pathway protects mice from elastase-induced experimental emphysema (35).

In contrast, β-catenin–dependent WNT signaling is upregulated in IPF, in which it seems to have a pathogenic role. Increased gene expression of WNT-1, WNT-7B, WNT-10B, FZD2 (frizzled class receptor 2), and FZD3 was revealed in IPF lungs, where they were located primarily in bronchiolar and alveolar epithelial cells. Likewise, increased nuclear β-catenin expression was detected in epithelial cells, indicating an active canonical pathway (36). Moreover, WISP1 (WNT1-inducible signaling protein 1) is increased, corroborating that functional WNT/β-catenin signaling activity is enhanced in this disease (37, 38). In this case, the excessive expression of the canonical WNT pathway also leads to impaired alveolar epithelial cell repair, contributing to the activation of fibroblasts and to extracellular matrix accumulation. Moreover (and quite the opposite to emphysema), in experimental models of lung fibrosis, the genetic or pharmacological inhibition of β-catenin signaling attenuated the fibrotic response induced by bleomycin (39, 40).


The neurogenic locus Notch homolog protein signaling is a highly conserved evolutionary pathway and plays a pivotal role in lung development during embryogenesis. Several Notch ligands, receptors, and downstream effector genes, such as HEY1 (Hairy/enhancer-of-split related with YRPW motif protein 1), HEY2, and HES5 (hes family basic helix-loop-helix transcription factor 5), are downregulated in smokers; more genes are downregulated in smokers with COPD than in healthy smokers (41). Although the effects of the decreased Notch signaling in this disease are unclear, recent evidence suggests that Notch1 protects against cigarette smoke–induced endothelial apoptosis via inhibiting the ERK (extracellular signal-regulated kinase) pathway (42). In addition, Notch1 reverses the limited proliferation, excessive apoptosis, and weak migration capacity induced by cigarette smoke on bone marrow–derived mesenchymal stem cells (43).

In sharp contrast, lungs from patients with IPF show evidence of hyperactive Notch signaling in honeycomb cysts, primarily in the epithelia comprised of ΔNp63/cytokeratin 5+ cells (44). Persistent Notch signaling after injury leads to parenchymal “microhoneycombing,” indicative of failed regeneration, and induces fibroblast-to-myofibroblast differentiation likely through the TGF-β (transforming growth factor-β)/Smad3 pathway (45). Supporting a profibrotic role, pharmacological repression of the Notch signaling pathway attenuates lung fibrosis in experimental models (46).

Sonic hedgehog

HH (hedgehog) signaling regulates key embryonic processes, such as cell growth, survival, differentiation, migration, and self-renewal. SHH (sonic hedgehog) is the most widely expressed Hedgehog gene, and it is involved in critical lung developmental processes. The SHH pathway cross-talks with TGF-β1 and has been consistently found to be upregulated in IPF. This may contribute to its pathogenesis by increasing fibroblast migration, proliferation, and survival, as well as to fibroblast–myofibroblast differentiation and exaggerated extracellular matrix production (47, 48).

In COPD, genetic variants of hedgehog-interacting protein (HHIP) result in reduced expression of this protein. HHIP is a repressor of Hedgehog ligands, suggesting that COPD may also present with an increase in SHH expression. However, this does not seem to be the case, as exemplified by experimental models. For example, deficiency of Hhip sensitizes mice to age-related spontaneous as well as cigarette smoke–induced emphysema (49, 50). Curiously, no significant changes in SHH are reported, suggesting that the effect of Hhip deficiency may depend on noncanonical Hedgehog pathways. Aging-associated emphysema in Hhip-haploinsufficient mice was provoked by increased oxidative stress (49), whereas the development of cigarette smoke–induced emphysema was related to increased CD8+ T-lymphocyte activation (50). Furthermore, no significant enrichment of SHH is observed in HHIP-silenced human bronchial epithelial cells (51).

Early-Life Events

A growing body of evidence indicates that alterations of prenatal and/or early postnatal lung development may affect lung function throughout life and, importantly, may increase the risk for developing COPD (52). A recent review that examined 16 studies addressing the impact of early-life insults in adult COPD corroborated that low birth weight, exposure to parental cigarette smoking in utero and in early life, and childhood respiratory disorders such as asthma and infections were associated with later development of COPD (53). Although the mechanisms are still uncertain, they may be associated with epigenetic reprogramming (see below). To our knowledge, there are no studies dealing with the likelihood that IPF susceptibility may be linked, at least in part, to some early-life insults.

Aging Mechanisms
Cell senescence

Although senescence of alveolar epithelial cells and fibroblasts has been described in COPD and IPF, several studies have revealed that in COPD, senescence is also prominent in endothelial and pulmonary artery smooth muscle cells; this has not been found in IPF (6, 54). Endothelial senescence may contribute to the progressive loss of alveolar architecture because normal function of endothelial cells is required for lung tissue repair.

Stem cell exhaustion dysfunction

Stem cell exhaustion/dysfunction and loss of tissue ability to self-repair are important drivers of aging. In COPD, DNA damage and senescence have been found in progenitor cells of the endothelial lineage (55). In addition, circulating hematopoietic and endothelial progenitor cells are decreased in COPD (56). Likewise, ex vivo evidence suggested that small airway epithelial basal cells from smokers with COPD are limited in their ability to regenerate a fully differentiated epithelium (57). More recently, it was shown that airway basal progenitor cell number, self-renewal, and multipotentiality are all decreased in COPD and, moreover, that depletion of basal progenitors relates to impaired lung function (58). Studies in IPF are scanty, but dissimilar stem/progenitor cells seem to be involved. In one study, dysfunction and impaired repair capacity of bone marrow–derived mesenchymal stem cells was described (59). Likewise, it has been found that the progenitor AEC2 cells from these patients are markedly decreased in number and show an impaired renewal capacity, likely associated with reduced expression of extracellular matrix glycosaminoglycan hyaluronan in the cell surface (60).


Autophagy is an essential catabolic process that delivers misfolded proteins and damaged organelles to the lysosome for degradation. A decrease in measured autophagic flux has been found in lung tissue homogenates from patients with IPF and in isolated IPF fibroblasts (61, 62). Persistent activation of phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin signaling contributes to decreased autophagy and to apoptosis resistance in IPF fibroblasts. By contrast, in patients with COPD, from the initial phases of the disease, a remarkable increase of autophagy has been observed that was evident throughout the disease’s progression (63).

Epigenetic Reprogramming

Epigenetic regulation, mediated by DNA methylation, histone modifications, chromatin remodeling, miRNAs, and long noncoding RNAs, is a critical player in physiology and pathology.

DNA methylation

Aging influences global epigenetic characteristics, and strong evidence indicates that during aging, there are tissue-specific and stochastic aging-associated gradual changes in DNA methylation (64). Importantly, the stochastic drift is not directional (there are hyper- and hypomethylations), is not uniform across the genome, and is quite variable between individuals of the same age. Within this context, patterns of IPF and COPD DNA methylation revealed to date show marked differences.

In COPD, differential methylation was found affecting CHRM1 (M1 muscarinic acetylcholine receptor implicated in nicotine dependence and bronchoconstriction of the airways), DTX1 (involved in natural killer T-cell development), GLT1D1 (glycosyltransferase 1 domain containing 1 that was found to be associated with reduced responses to leukotriene modifiers in the treatment of asthma), and C10orf11 (previously found to be associated with lung function). Among the top differentially methylated genes, three were transcription factors: HNF1B (hepatocyte nuclear factor-1β), FOXK1 (forkhead box protein K1), and FOXP2 (65).

An integrative study of whole-genome methylation and allelic association analyzed how cis-meQTLs intersected with subthreshold and genome-wide significant gene variants identified in previous GWASs (66). The association between gene expression and DNA methylation showed associations for KCNK3 (potassium two pore domain channel subfamily K member 3), SULT1A2 (sulfotransferase family 1A member 2), and NUPR1 (nuclear protein 1, transcriptional regulator), indicating a possible gene-regulatory role for the genetic control of DNA methylation in lung tissue.

In IPF, studies on global analysis of DNA methylation profiles are scanty. In one study using comprehensive high-throughput arrays for relative methylation, meaningful methylation modifications were found that were predominantly located in gene bodies and CpG island shores (67). Among the most enriched canonical pathways were several that have been implicated in the pathogenesis of IPF, such as CXCR4 signaling, thrombin signaling, Wnt/β-catenin signaling, and epithelial adherens junction signaling. Analysis of binding motifs in promoters identified overrepresentation of regulators of lung development, specifically β-catenin, GLI1, and FOXC2, supporting an important role of the recapitulation of developmental pathways in this disease (38). Although enrichment in cis relationships was observed, methylation marks that regulate large groups of genes were also identified, and four of the most significant trans-regulating methylation marks were near transcription factors (CASZ1, FOXC1, MXD4, and ZDHHC4). Therefore, comparison of DNA methylation changes in both diseases shows marked differences.


miRNAs are endogenous noncoding RNAs that serve as key post-transcriptional regulators in multiple biological processes, whereas their dysregulation is implicated in many diseases. Dysregulation of numerous miRNAs has been reported in COPD, but with discrepant results. For example, in some studies, most miRNAs were found to be downregulated, whereas in others, most of them were upregulated (6870). Some dysregulated miRNAs affect the TGF-β signaling pathway as well as the inflammatory response, neutrophil infiltration, and reactive oxygen species generation (68, 71). Interestingly, comparison of the expression of miRNA concentrations in bronchial epithelial cells from current smokers and never smokers revealed that 28 miRNAs were differentially expressed; most of them were downregulated in smokers (72). Similarly, mice exposed to cigarette smoke showed remarkable changes, mostly downregulation (73).

In IPF, numerous dysregulated miRNAs have also been reported, and up- and downregulated miRNAs appear to result in the overexpression of several meaningful profibrotic genes and pathways (38, 74). In general, the dysregulated miRNAs in IPF and COPD described so far are mostly different, although both diseases share a few of them. For example, a regulatory network using genes differentially expressed in both diseases revealed an increase of miRNA-96 in COPD and IPF tissues, which may contribute to the similar altered p53/hypoxia pathway through post-translational deregulation (23). Interestingly, some changes in the opposite direction have also been documented. For example, miRNA-17-92 is downregulated in IPF and upregulated in COPD (75). The miR-17-92 cluster targets several components of the TGF-β pathway and is critically important in lung epithelial cell development (76, 77). However, it is difficult to compare the contribution of miRNA dysregulation in the pathogenesis of IPF and COPD, because they have overlapping functions whereby several miRNAs can regulate a single gene and multiple genes are affected by a single miRNA.

Why Do Some Patients Develop IPF and Emphysema? Causality or Chance?

There is increasing recognition of the coexistence of emphysema and IPF, although whether it represents a distinct clinical entity as well as the pathogenic mechanisms remain unclear. Moreover, whether these two conditions are causally linked is uncertain. One possibility is that they have a genetic architecture sharing susceptibility genes for both diseases (causal relationship). In this context, some light is shed by the study of telomere syndromes. Mutations in several telomerase genes have been linked to familial emphysema and to IPF, where the lung disease phenotype (fibrosis or emphysema or both) may depend on some distinctive gene–environment interactions. For example, within a single family, it has been shown that never smokers that carried the mutation developed pulmonary fibrosis, whereas smokers (mainly females) were at high risk for emphysema (7, 78). In the same studies, it was shown that few patients developed both diseases, suggesting that they share a genetic etiology and as yet unclear environmental and other host factors. Whether the same occurs in sporadic combined IPF and emphysema is largely unknown.

The other possibility is simply random chance (casual relationship; e.g., bias of Berkson); COPD and IPF rise on parallel roads with aging, and both occur primarily in smokers. However, the prevalence of IPF within the total population is low, with about 10 in 10,000 diagnosed with this disease after the age of 75 years (79). By contrast, COPD is remarkably more frequent; around 1,200 in 10,000 are diagnosed with this disorder after the age of 65 years (80). Therefore, if 12% of the general population over 65 years will have COPD, at least 12% of patients with IPF may also develop COPD. However, the prevalence of emphysema coexisting with IPF is significantly higher and may reach 30% of patients (81).

Supporting the notion that IPF and COPD may represent two different diseases running in parallel in the same individual is the observation that combined pulmonary fibrosis and emphysema can occur with similar frequency in nonsmokers with other non-IPF inflammation-driven fibrotic lung disorders, such as connective tissue diseases and chronic hypersensitivity pneumonitis (82, 83). Moreover, both diseases seem to be compartmentalized in the same patient, with emphysema usually occurring in the upper zones of the lungs, whereas fibrosis occurs in the lower zones.

Conclusions and Future Directions

IPF and COPD are two complex, progressive, and irreversible chronic respiratory diseases. In both, aging is a driving force, and actually, most of the key aging mechanisms exaggeratedly occur in the lungs in both diseases. However, the pathology and behavior are radically different. This likely reflects the complex interactions between genetic architecture and the epigenetic reprogramming that influence the lung during aging. This may result in multiple altered pathways that are differentially regulated between both diseases. In addition, differences in the genetic background and/or epigenetic changes may lead to differences in the initial target cell type as well as in the cellular and molecular responses to environmental exposures, including tobacco smoke.

To define the differences that explain why an individual develops one or the other, several future approaches are necessary. First, GWAS and epigenome-wide association studies, as well as analysis of aging signatures, should compare both diseases directly in the same study. Without direct comparison, reporting bias could explain some of the differences highlighted in this pulmonary perspective article. Likewise, animal models, although they do not completely recapitulate these human diseases, should be used in more creative ways and with novel interdisciplinary approaches to address the age-dependent differences between COPD and IPF, as well as the contributions of the genetic architecture and/or epigenetic reprogramming. In this context, to mimic the interactions of aging with COPD and/or IPF, the timing of phenotype onset in the models should resemble more closely that of these diseases, including risk factors related to the early-life environment, sex as a biological variable, and genetic and epigenetic modifications. A critical approach is to identify which specific cell types are affected. There is some evidence indicating that in IPF, most of the aging-associated alterations, such as telomere attrition, senescence, and mitochondrial dysfunction, occur primarily in AEC2 cells. By contrast, in COPD, airway epithelial cells and endothelial cells are also affected. Understanding the cellular and molecular mechanisms underlying both diseases will shed light on the most influential events that should be therapeutically targeted to halt the progression and ultimately reverse these degenerative processes.

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Correspondence and requests for reprints should be addressed to Moisés Selman, M.D., Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502, CP 14080, Mexico City, Mexico. E-mail: .

*Participation complies with American Thoracic Society requirements for recusal from review and decisions for authored works.

Originally Published in Press as DOI: 10.1164/rccm.201806-1166PP on September 13, 2018

Author disclosures are available with the text of this article at


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