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Lung Function Trajectories: a New Framework to Understand Adult Chronic Respiratory Diseases

Lungs grow and mature in utero and after birth until early adulthood. Normally, lung function reaches a peak between 20-25 years of age, earlier in females, and after a relatively brief plateau , it declines slowly due to physiological lung ageing. There are several genetic and environmental factors with the potential to alter this normal lung function trajectory, so it is now recognized that in the general population there is indeed a range of them. Further, it is also known now that some of these trajectories have important health consequences, both for the lungs but also for other organ systems, including premature death. Here we provide a brief overview of these new concepts and discuss the potential implications of this new framework to understand adult respiratory diseases.


INtrODUctION
Lung development and growth is extremely complex 1 . It starts in utero and continues after birth, during infancy and adolescence until early adulthood (Fig. 1), where lung function reaches a peak value (earlier in females) 2 . After a relatively brief plateau, lung function declines moderately due to physiological lung ageing 3 . This normal lung function trajectory can be altered by several genetic and environmental factors. Indeed, it is now well recognized that there is a range of them in the general population 3,4 (Fig. 1). Further, it is also now known that some of these trajectories can have important health consequences, both for the lungs and for other organ systems such as the cardiovascular and metabolic ones, including premature death 5,6 (Fig. 2). Below we briefly review the evidence supporting this new paradigm and discuss its potential implications for the understanding of adult chronic respiratory diseases.

LUNG FUNctION trAJEctOrIEs
Altered lung growth Between 4-12% of individuals in the general population fail to reach a forced expiratory volume in one second (FEV 1 ) peak in early adultwood within the predicted "normal range" for their age and sex 5 . This can be due to one or more genetic risk factors [7][8][9] and/or environmental conditions in utero and after birth 4,10 , including maternal tobacco smoking and under-nourishment, premature birth, intrauterine growth restriction and broncho-pulmonary dysplasia, air pollution exposure, lower respiratory tract infections and active smoking during adolescence. Childhood "asthma" is also often considered a risk factor for low lung function in early adulthood 11 but the diagnosis of "asthma" in young children is difficult to establish objectively and, although the presence of "asthma" can conceivably impair lung growth, it is also possible that any other process impairing lung growth can cause similar, nonspecific, symptoms than those traditionally associated to asthma (dyspnoea, cough, wheezing). These environmental risk factors interact in a complex manner and change with time 12 (Fig. 3). Importantly, many of them are preventable 12 . Finally, it is also important to note that individuals who fail to attain a normal peak lung function in early adulthood suffer a higher prevalence and about a decade earlier incidence of cardiac and metabolic comorbidities, as well as premature death 5 . These observations have been later reproduced in other cohorts 13 .

Accelerated lung function decline
Chronic obstructive pulmonary disease (COPD) has been traditionally considered the paradigm of an adult respiratory disease characterized by an enhanced rate of lung function decline 14 due to the inflammatory response to tobacco smoking 6 . Recent research, however, has shown that this paradigm is incomplete 6 since about 30% of COPD patients worldwide are never smokers 15 , exposure to other inhaled particles and gases than those of smoking (e.g. biomass, air pollution) can also lead to COPD in adulthood 16 , and not all patients with COPD exhibit enhanced lung function decline 17,18 . The latter was clearly shown in a recent study by Lange, Celli, Agustí et al. in three large independent cohorts 18 . Results showed that the rate of lung function decline was accelerated in only about half of adult COPD patients whereas the other half had evidence of low peak lung function in their thirties and developed COPD with a normal lung function decline rate 18 . These observations have been confirmed by other subsequent studies [19][20][21][22] . Further, a recent analysis in the Framingham Offspring Cohort and their direct descendants (Gen III cohort) has provided evidence of trans-generational reproducibility of lung function 5 (Fig. 4), albeit it should be noted that this transgenerational reproducibility may be due to genetic and/or shared environmental factors.

IMPLIcAtIONs FOr A NEW UNDErstANDING OF ADULt cHrONIc rEsPIrAtOrY DIsEAsEs
The realization that several genetic and environmental risk factors interact dynamically over time in very complex ways (Fig. 3) and that, as a result, there is a range of lung function trajectories in the general population ( Fig. 1), some of them with important health consequences, including premature death (Fig. 2), raises questions and challenges and, at the same time, opens new opportunities for prevention and early intervention of chronic respiratory disease in children and adults 23 .
First, the biological mechanisms underlying these different lung function trajectories are not always well understood. In terms of defective lung growth, the two main, non-mutually exclusive, mechanisms proposed 3 include abnormal lung development in utero (since about 40% of lung function deficits at 6-7 years of age are already present at birth 24 ) and failure to "catch-up" lung function during infancy and adolescence 25 (the term catch-up here refers to the observation that many environmental conditions cause growth impairment but, when they resolve, some (not all) children regain a normal growth trajectory 26,27 ). On the other hand, in terms of enhanced lung function decline in adulthood, albeit oxidative stress, protease-antiprotease imbalance and an abnormal inflammatory response have been traditionally considered their main underlying biological mechanisms 28 , now we know that many other ones also participate, including cellular senescence and apoptosis, airway fibrosis and remodelling, stem cell exhaustion, extracellular matrix alterations, autophagy, autoimmunity to neo-epitopes and reductions of endogenous anti-ageing molecules 6 . In essence, it is the interplay between two major biologic mechanisms, organ development, maintenance and repair (green triangle in figure 5, which decreases with age), and cumulative tissue injury and ageing (red triangle in figure 5,   figure 5), including lung function trajectories ( Fig. 1) and associated comorbidities (Fig. 2). Of note, due to gene-environment interactions (Fig. 3), the slope of these two main mechanisms (green and red triangles in figure 5) may change (for better or worse) in different individuals (as indicated by the dashed arrows, green and red, in figure 5). Understanding much better the role and interactions of all these putative mechanisms may open new therapeutic alternatives to promote lung growth and stop lung function decline 29 .
Second, it is conceivable that, if for whatever genetic and/or environmental factors reviewed above the lungs do not develop properly, other organ systems may do so too. After all, genes are the same in all cells and many environmental factors (e.g., smoking, pollution, diet, exercise,…) can affect many other organs than the lungs. In fact, several genetic variants associated with lung function are also associated with birth weight and height as well as with cardio-metabolic risk 30,31 . Collectively, these observations indicate that low peak lung function in early adulthood may be a warning sign of abnormal development and dysfunction in other systemic organs. If so, spirometry may actually become a reliable, reproducible, non-invasive and cheap method to identify high-risk individuals with disordered lung development (and, potentially, other organ systems too), who   5 . Smoking had an additive but independent effect on mortality, and we did not find statistically significant differences in cause-specific mortality between high and low lung function groups, but there was a numerically higher cardiovascular mortality in participants with low lung function 5 . We also explored this relationship in an independent cohort (Coronary Artery Risk Development in Young Adults Study [CARDIA]) and found that all-cause mortality before the age of 50 years in CARDIA participants with low lung function in early adulthood was three times higher than that of people with normal lung function ( (2) the rather small number of participants included in the two COPD trajectories (65 versus 79); (3) a potentially confounding effect of medications, which was not considered in the analysis; and, (4) the lack of imaging data or diffusing capacity for carbon monoxide (DL CO ) measurement, which may have helped to assess the proposed influence of emphysema. In any case, these three studies 5,13,32 clearly indicate that there is a significant association between lung function trajectory and mortality risk.
Fourth, in relation to prevention and treatment, it is well established that quitting smoking reduces the rate of lung function decline 2,34 and that several other interventions can potentially prevent abnormal lung development, such as decreasing exposure to air pollutants (including maternal smoking) during pregnancy, childhood and puberty 4,20,35 , close follow-up of survivors of very preterm birth 36 , encouraging immunization and developing better vaccines against acute infant viral diseases 4,20 , promoting physical activity [37][38][39] and healthy diet [40][41][42] , including vitamin A 42 and vitamin C 43 supplementation. CC16 is being investigated as a potential therapeutic target in this setting 44,45 .
A final comment relates to the observation that about 12% of the general population may follow a "supranormal" lung function trajectory 20 (Fig. 1). If exposed to noxious environmental conditions, these individuals may have lost lung function and still remain within the normal range 6 . Potentially, this can contribute to explaining the apparent paradox of identifying individuals with symptoms and/or evidence of lung damage (emphysema) with preserved spirometry 6 .
cONcLUsIONs Several genetic and environmental risk factors conspire to generate a range of lung function trajectories through life, and some of them are associated with significant implications for health and disease. A better understanding of the biological mechanisms underlying these trajectories may help prevent and/or treat them. However, we need to act earlier 46 . Promoting the use of spirometry in schools may be a good alternative for that 46 . In this context, spirometry can act as a "canary in a coal mine" 47 . After all, remember that a key spirometric variable is the "vital" capacity 48 . What a name!

DIscLOsUrEs
Dr. Agusti reports grants and personal fees from GSK, Menarini, Chiesi, AZ; and personal fees from Zambon; all outside the submitted work. Dr. Agustí is the editor in chief of BRN Reviews; the journal's editorial procedure to ensure impartial handling of the manuscript has been followed. Dr. Faner Canet reports grants from GSK and Menarini; all outside the submitted work.