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Assessment of dietary fat intake and innate immune activation as risk factors for impaired lung function

Abstract

Background/objectives:

Preservation of lung health with aging is an important health issue in the general population, as loss of lung function with aging can lead to the development of obstructive lung disease and is a predictor of all-cause and cardiovascular mortality. Inflammation is increasingly linked to loss of lung function and evidence suggests that consumption of dietary fat exacerbates inflammation. We aimed to determine the association between dietary fat intake and lung function in older people.

Subjects/methods:

Participants from the Hunter community study, a population-based cohort, were recruited during 2004 and 2005. Participants received a clinical assessment, including spirometry, and provided a blood sample. Diets were analyzed using food-frequency questionnaires. Plasma interleukin (IL)-6 and C-reactive protein was measured by Enzyme-Linked immunosorbent assay.

Results:

Using backward stepwise linear regression, %energy from dietary fat, age and plasma IL-6 were considered as negative predictors of forced expiratory volume in one second (FEV1) in men. Also in men, %energy intake from dietary fat, age, body mass index and IL-6 were negative predictors of %predicted forced vital capacity (FVC). Smoking and age were negative predictors of FEV1/FVC. In women, plasma IL-6 and age were negative predictors of %FVC, whereas obesity was positively associated with FEV1/FVC.

Conclusions:

An increased proportion of fat in the diet is associated with the reduced lung function in older men. Dietary-fat induced innate immune activation and IL-6 release may contribute to this effect. Dietary interventions involving fat restriction should be further investigated as means of preserving lung function with aging.

Introduction

Preservation of lung health is an important health issue in the general population. Lung function progressively declines with aging (James et al., 2005) and can lead to the development of obstructive lung diseases (OLDs), such as asthma and chronic obstructive pulmonary disease (COPD), which represent a significant and increasing global health problem (Buist et al., 2007). Several studies have also shown that low or declining lung function, measured by forced expiratory volume in one second (FEV1) or forced vital capacity (FVC), is a strong predictor of all-cause (Hole et al., 1996) and cardiovascular mortality (Tockman et al., 1995; Schroeder et al., 2003).

The factors leading to lung function decline with age are not well understood (James et al., 2005). Both smoking and asthma accelerate lung function decline (James et al., 2005). However, lung function also declines in the absence of these exposures, suggesting that other risk factors are important (Buist et al., 2007). Lung function is inversely associated with systemic inflammatory mediators, such as interleukin (IL)-6 (Donaldson et al., 2005) and C-reactive protein (CRP) (Aronson et al., 2006). Thus, systemic inflammation may be an important mechanism contributing to the loss of lung function, and the development of OLD and other chronic diseases, such as cardiovascular disease (CVD).

There are several mechanisms that may link lung health to systemic inflammation. Exposure to noxious particles, such as cigarette smoke and occupational chemicals, leads to activation of airway-resident macrophages, which release inflammatory mediators and cytokines, resulting in airway inflammation. It is possible that systemic dissemination of local lung inflammation then occurs, in an ‘overspill’ effect (Wouters, 2005). Various features of respiratory disease, particularly in relation to COPD, may lead to systemic inflammation. For example, tissue hypoxia and sedentarism may lead to the production of inflammatory mediators by skeletal muscle (Maclay et al., 2007). Subclinical respiratory tract infection (Wilkinson et al., 2006) may also contribute to chronic systemic inflammation.

In addition, systemic inflammation results from the dietary fat consumption (Nappo et al., 2002; Aljada et al., 2004), which directly stimulates the innate immune response, by mechanisms, such as activation of toll-like receptor 4 by circulating free fatty acids (Shi et al., 2006). This can lead to a systemic inflammatory response, including increased circulating levels of pro-inflammatory mediators, such as IL-6 (Nappo et al., 2002), tumour necrosis factor alpha (Nappo et al., 2002) and CRP (Aljada et al., 2004). IL-6 is a potent inducer of neutrophil responses, which are closely linked to the development of airflow obstruction (AFO) (Shaw et al., 2007). IL-6 and neutrophil responses are also typical features of innate immune activation, which can be persistently activated in neutrophil mediated airway diseases (Simpson et al., 2007).

The contribution of dietary fat to lung function decline is unknown. In this paper we examine the hypothesis that dietary fat stimulates innate immune activity, which results in systemic inflammation and lung function impairment in the general population. We aimed to examine the association between dietary fat and lung health, including %FEV1, %FVC and FEV1/FVC.

Subjects and methods

Study participants

Participants for the current investigation came from the Hunter community study, which is a population-based cohort study of men and women aged between 55–85 years in Newcastle, Australia (Duke et al., 2007). Participants were randomly selected from the NSW State Electoral Roll. Recruitment for the study took place during 2004 and 2005. All participants received a clinical assessment, including spirometry, and provided a blood sample. This sub-study involved 195 subjects who were selected for a nested case–control study examining the predictors of impaired lung function. A nested–case–control study is the one in which cases of the disease and the healthy controls are selected from a defined cohort rather than from the general population. Cases (n=45) were all subjects from the Hunter community study with low lung function (FEV1<80%) and controls were subjects from the Hunter community study without low lung function matched to the cases so that they had a similar age and sex profile. Subject characteristics are described in Table 1. Written informed consent was obtained. The study was approved by the University of Newcastle and Hunter New England Human Research Ethics Committees.

Table 1 Subject characteristics by gender

Spirometry

Spirometry was done using electronic spirometers (Micro Medical SpiroUSB, Cardinal Health, Kent, UK) with Spida 5 software (Carefusion Ltd, Kent, UK) and predicted values of Gore (Gore et al., 1995). Key lung function measures were FEV1 and FVC. Height was measured using wall-mounted stadiometer and weight was measured using scales accurate to the nearest 0.1 kg. Body mass index (BMI) was calculated as weight (kg) per height (m)2.

Analysis of Plasma IL-6 and CRP

Blood was collected in EDTA tubes and centrifuged at 4 °C and 3000 g, for 10 mins to separate plasma, which was stored at −80 °C before analysis. Plasma IL-6 concentrations were analyzed by commercial Enzyme-Linked immunosorbent assay (R&D systems, Minneapolis, MN, USA). CRP concentrations were analyzed by commercial Enzyme-Linked immunosorbent assay (MP-Biomedicals, Solon, OH, USA).

Dietary intake

Dietary intake was assessed at baseline using a self-administered, semiquantitative food questionnaire, validated as previously described (Smith et al., 1998). Nutrient intakes were determined by a custom-made nutrient analysis programme based on NUTTAB 2006 database (Food Standards Australia New Zealand, 2006).

Statistical analysis

Statistical analyses were performed using SAS Version 9.2 (SAS institute, NC, USA) and Stata 9.1 (Stata Corp LP, College Station, TX, USA). Our hypothesis assumed that dietary fat stimulates innate immune activity, which is reflected by increases in systemic IL-6 levels and hepatic CRP production. This is also associated with the increased innate immune responses in the lung, resulting in lung function impairment. The relationship between IL-6 and %FEV1 was much stronger than the relationship between CRP and %FEV1 so our analysis has focused on IL-6. We examined the associations between lung function (%FEV1, %FVC and FEV1/FVC as outcomes) and risk factors for inflammation, including dietary fat intake (total energy intake, total fat, %energy from dietary fat, total saturated fatty acids, total monounsaturated fatty acids, n-3 polyunsaturated fatty acids (n-3 PUFAs) and n-6 polyunsaturated fatty acids), obesity (BMI, waist to hip ratio) and innate immune activation (IL-6) (as predictors) after adjusting for gender, age and smoking status (never, former, current) using linear regression. The strength of the univariate association between each factor and the lung function variable was assessed by the value of coefficient of determination (R2) in a simple linear regression model. Similarly, the strength of the relationship between all risk factors and the outcome was assessed by the R2 value from a multiple regression model that included all factors. R2, which is also known as the coefficient of determination, can be interpreted as the amount of variation in the outcome variable that is explained by the predictor variables in the linear regression model (Pagano and Gauvreau, 2000). Backward stepwise regression was used to create a parsimonious model and the final models were confirmed with forward stepwise regression. The relative importance of each predictor in the final model was judged by examining its partial correlation to the outcome after adjusting for all other variables in the final model.

Results

The characteristics of the 195 subjects selected for this study are described in Table 1 separately by gender. %Energy from dietary fat, plasma IL-6 and obesity (BMI and waist to hip ratio) were all found to be associated with the reduced %FEV1 in men in a linear regression model (Table 2). Other dietary variables, including total energy intake, total fat, total saturated fatty acids, total monounsaturated fatty acids, n-3 PUFA and n-6 polyunsaturated fatty acid were not significantly associated with %FEV1 in men or women. Age, %fat intake and plasma IL-6 remained statistically significant predictors of %FEV1 among men in a stepwise regression model (Table 3 and Figures 1a and b). In combination, these three variables explained 30% of the total variation in %FEV1. Each one-point increase in dietary fat as a percentage of total energy was associated with a reduction in %FEV1 of 1.1% and each one pg/ml increase in plasma IL-6 was associated with a reduction in %FEV1 of 9.8. Age, %energy intake from dietary fat, plasma IL-6 and BMI were negative predictors of %FVC in men (Table 3, Figures 2a–c) and age and IL-6 were negative predictors of %FVC in women (Table 3). Smoking and age were found to be negative predictors of FEV1/FVC in men and BMI was a predictor of FEV1/FVC in women (Table 3).

Table 2 Percent of variation (as measured by R2) in %predicted FEV1, %predicted FVC and FEV1/FVC explained by each factor in a simple linear regression model for men and women separately
Table 3 Coefficients of variables remaining in the backward stepwise linear regression models with %FEV1, FEV1/FVC and %FVC as the outcomes of interest, and using a significance level of 0.15 as the cut point to stop excluding variables from the model
Figure 1
figure1

Distribution of %FEV1 in men by (a) quartile of dietary fat as a percentage of total energy and (b) quartile of IL-6.

Figure 2
figure2

Distribution of %FVC in men by (a) quartile of dietary fat as a percentage of total energy and (b) quartile of IL-6 and (c) quartile of BMI.

We further explored IL-6 and %dietary fat as predictors of %FEV1, in particular to see if one of these variables was the mediator of the association with %FEV1 for the other. The partial correlation coefficient of IL-6 with %FEV1 after removing the effect of the dietary fat as a percentage of total fat was very similar to the crude correlation coefficient. Similarly, the partial correlation coefficient for dietary fat was similar to the crude correlation and therefore, it appears that the effects of the two variables are independent.

Discussion

Lung function decline with aging is an important global health problem, as it can lead to the development of OLD and is also a risk factor for CVD events (Tockman et al., 1995; Schroeder et al., 2003) and all-cause (Hole et al., 1996) mortality. Our study is the first to show that the proportion of total fat in the diet is important to lung health. We have shown that an increased proportion of fat in the diet is associated with reduced lung function (%FEV1 and %FVC) in men. In addition, innate immune activity, reflected by plasma levels of IL-6, was inversely associated with both %FEV1 and %FVC in men and %FVC in women.

Our observations are supported by several studies that have suggested that dietary fat may be related to poor respiratory outcomes. High total fat intake has been shown to be related to bronchial hyperresponsiveness (Soutar et al., 1997) and incidence of asthma in men (Strom et al., 1996) and plasma triglycerides have been shown to be elevated in subjects with adult-onset wheeze (Bodner et al., 1999). A ‘western’ versus ‘prudent’ dietary pattern, which included higher intake of saturated- and trans-fatty acids, was associated with a higher risk of COPD (Varraso et al., 2007). Furthermore, a ‘meat–dim sum’ versus ‘vegetable–fruit–soy’ dietary pattern, was associated with high saturated fat intake, increased the risk of developing cough with phlegm (Butler et al., 2006).

We hypothesized that, a high dietary fat intake would be associated with reduced lung function because of innate immune activation. To examine this hypothesis, we examined lung function parameters across a range of dietary fat intakes, with the median fat intake ranging from 19.0–46.6% of total energy. Thus, subjects with the highest fat intakes were consuming a proportion of fat that is well above the dietary recommendations of 20–35% energy from fat (US Department of Health and Human Services and US Department of Agriculture, 2005). Various pro-inflammatory mediators increase following a high fat challenge (reviewed in Wood et al., 2009). A number of studies have shown that a meal with fat content ranging from 50–140 g, representing 30–64% total energy, causes oxidative stress and inflammation (Mohanty et al., 2002; Nappo et al., 2002, Aljada et al., 2004; Jellema et al., 2004; Blackburn et al., 2006; Patel et al., 2007). In chronic studies, the evidence is more heterogeneous, with most studies of fat intake having been conducted during weight loss interventions. However, in studies where subjects were in energy balance, a high fat diet (40–60% fat) led to a decrease in flow-mediated vasodilation (Leighton et al., 2000), but no change in inflammatory markers (Volek et al., 2003; Meksawan et al., 2004). Interestingly, a study of fat intake in athletes showed that a low fat (15%), high carbohydrate (65%) diet increased inflammation (IL-6) and decreased the anti-inflammatory response (IL-2) to exercise, and this was reversed by increasing the proportion of dietary fat consumed (Venkatraman and Pendergast, 1998). Thus, dietary patterns may have different effects on inflammation in different subject groups. We found that in the general population, %fat and innate immune activation are risk factors for low lung function in men.

The innate immune system is known to be important to respiratory health. Asthma involves a heterogeneous inflammatory response, with activation of both the acquired and the innate immune systems (Simpson et al., 2007). Innate immune activation leads to an IL-8-mediated neutrophilic airway inflammation (Simpson et al., 2007). It is likely that this pathway is important for lung function decline, as it has previously been shown that impaired innate immune function results in airway inflammation, with increased neutrophils and neutrophil elastase being observed in the airways of elderly people (Berend, 2005). In our study we assessed plasma levels of IL-6, as a circulating marker of innate immune activation. Plasma IL-6 is a clinically relevant marker of innate immunity, and has been shown to be a useful prognostic marker of cardiovascular outcomes in some epidemiological studies (Ridker et al., 2000). Increased circulating IL-6 levels are also observed in respiratory disease. Plasma IL-6 is elevated during asthma exacerbation (Yokoyama et al., 1995), and blood cells from asthmatics release more IL-6 than controls after a challenge with specific innate immune receptor agonists (Bettiol et al., 2000). In established COPD, IL-6 levels rise over time as lung function declines, with the rise in IL-6 being greater in subjects with more frequent exacerbations (Donaldson et al., 2005). In some settings, such as following exercise, IL-6 may have an anti-inflammatory role, as skeletal muscle produces high concentrations of IL-6, which appears to inhibit tumour necrosis factor alpha production and thereby tumour necrosis factor alpha-induced insulin resistance (Pedersen et al., 2003). Nonetheless, in OLD, IL-6 maps the inflammatory process and may be an important marker of disease progression.

Circulating CRP has also been shown to be elevated in OLD, including non-allergic asthma (Olafsdottir et al., 2005) and COPD (Gan et al., 2004). Importantly, both IL-6 and CRP are elevated following consumption of dietary fat (Nappo et al., 2002; Aljada et al., 2004) and are thus relevant to our hypothesis. However, as our data indicated that the relationship between IL-6 and %FEV1 was much stronger than the relationship between CRP and %FEV1, our analysis focused on IL-6. We observed a strong inverse relationship between IL-6, %dietary fat and both %FEV1 and %FVC in men, suggesting that dietary fat intake and activation of the innate immune response are associated with low lung function.

Interestingly, there was no statistically significant association between dietary fat intake and IL-6 or CRP in men or women. This may be explained by the fact that there are many factors influencing these biomarkers, such as infection, smoking, age and physical activity. If fat intake was the only factor contributing to IL-6 levels, then adding IL-6 to the same model as fat intake would remove the effect of fat intake, as it would be the intermediate for the fat effect. The fact that fat intake and IL-6 both stay in the model indicates that fat must be mediating its effect, at least partly, through some factor other than IL-6.

The inflammatory effects of dietary fat depend on the quality of the fat consumed. Several epidemiological studies have suggested that n-3 PUFA intake may improve lung function (Schwartz and Weiss, 1994). It has also been suggested that the ratio of n-3:n-6 polyunsaturated fatty acid consumed is important in the development of inflammatory lung disease, as consumption of n-3 PUFA leads to a reduction in the cellular content of n-6 polyunsaturated fatty acid, which is the substrate for pro-inflammatory eicosanoids. However, in our study, n-3 PUFA intake was not found to be associated with %FEV1 in the linear regression model. Trans-fatty acids have been shown to have pro-inflammatory properties, and have also been related to increased prevalence of childhood asthma and allergies (Weiland et al., 1999). We were unable to assess the trans-fatty acid intake in our population, because of a lack of data on the trans-fatty acid content of Australian foods. Nonetheless, our study supports the hypothesis that overall fat intake is important for lung health in men, as we have observed that obtaining a high proportion of energy from total fat is associated with poor lung function.

Previous studies have shown that obesity is negatively associated with lung function in healthy adults (Lazarus et al., 1997). In our study, obesity (both BMI and waist-to-hip ratio) was a significant negative predictor of %FEV1 and %FVC in men in the simple linear regression model. However, in the backward stepwise linear regression model, obesity dropped out of the model for %FEV1 and age, %dietary fat and IL-6 remained as negative predictors. In the model for %FVC, BMI remained as a negative predictor, in addition to age, %dietary fat and IL-6. A high fat intake is common in obese individuals, and both fat intake and adipose tissue provide direct sources of systemic inflammation. However, our data suggest that fat intake should be assessed separately and may be a stronger risk factor for impaired lung function in men. In women, neither dietary fat nor obesity was significantly associated with lung function. It is uncertain why the importance of dietary fat and obesity would differ with gender. However, it should be noted that there were less females than males in our study (74 versus 121 respectively), thus the models in females had less power to detect significant effects of various dietary components. Further studies are needed to explore the effect of dietary fat intake on lung function in males versus females.

Airflow obstruction, often assessed using the ratio FEV1/FVC, is another important measure of lung health. FEV1/FVC <70% is used to define COPD. In our study, predictors of low FEV1/FVC were smoking in men and low BMI in women. Smoking is well established as a cause of AFO and is the primary cause of COPD. However, the relationship between obesity and AFO is less clear. Although obesity has previously been reported to be negatively associated with FEV1 in healthy adults (Lazarus et al., 1997), the relationship between obesity and AFO is complex. In COPD, the ‘obesity paradox’ is observed, where BMI>24 kg/m2 has been associated with improved survival rates and less severe AFO (Schols et al., 1998; Celli et al., 2004). Thus it has been suggested that obesity may have a protective effect against the development of AFO, which is in agreement with the model of FEV1/FVC in women in our study. Dietary fat was not a risk factor for low FEV1/FVC in men or women suggesting that, fat intake has a greater effect on loss of lung function than the development of AFO.

Although several studies have shown a link between impaired lung function and CVD (Tockman et al., 1995; Schroeder et al., 2003), the mechanisms behind this link are unclear. Systemic inflammation is associated with both OLD and CVD, which suggests that an inflammatory environment contributes to the progression of both these diseases. However, a recent study showed that the inverse relationship between systemic inflammation (CRP) and pulmonary function also occurs in apparently healthy subjects, without pulmonary disease and with no smoking history (Aronson et al., 2006). As low lung function is accompanied by low-grade inflammation even in the preclinical stage of OLD, the prolonged period of lung function decline that occurs with aging means that individuals have long-term exposure to pro-inflammatory mediators, which is likely to contribute to CVD development.

Limitations of this study include the relatively small sample size and the use of food-frequency questionnaires to determine the dietary intake. Use of weighed food records would provide more accurate dietary intake data, however, food-frequency questionnaires are the most practical option in a large community-based study. The cross-sectional nature of the analysis is also a limitation and a longitudinal study is warranted to establish a causal effect of dietary fat on innate immunity and lung function over time.

Ageing is a global research priority and airflow limitation and CVD are large and increasingly prevalent health problems worldwide. Thus, it is critical that the determinants of decline in lung function within an older population are understood. The results of this study suggest that dietary fat restriction should be further explored as a strategy for preventing lung function impairment with the ageing, particularly in men. This may have the potential to decrease both respiratory and CVD risk.

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Acknowledgements

The authors would like to acknowledge the assistance of the Hunter Community Study staff who collected the samples and the staff in Respiratory and Sleep Medicine, Hunter Medical Research Institute (HMRI), who carried out the Enzyme-Linked immunosorbent assay analysis. The study was supported by an HMRI grant from the Greaves family. LGW is a recipient of a University of Newcastle Brawn Fellowship. PGG is a recipient of a Practitioner Fellowship from the National Health and Medical Research Council, Australia.

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Wood, L., Attia, J., McElduff, P. et al. Assessment of dietary fat intake and innate immune activation as risk factors for impaired lung function. Eur J Clin Nutr 64, 818–825 (2010). https://doi.org/10.1038/ejcn.2010.68

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Keywords

  • dietary fat
  • IL-6
  • lung function
  • inflammation
  • obstructive lung disease

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