Neutrophils and low-grade inflammation in the seemingly normal aging human lung

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Abstract

Lung function deteriorates with age and is associated with elastin loss, loss of elastic recoil and decline in diffusing capacity for carbon monoxide. To determine whether increased numbers of neutrophils can be found in the lower respiratory tract in healthy, clinically normal individuals who are more advanced in age, we performed bronchoalveolar lavage (BAL) on individuals in three discontinuous age groups (Group I, 19–36 years; Group II, 45–55 years; Group III, 64–83 years). We found that neutrophils were increased in many individuals in Group III compared to Group I. The neutrophil cell differential count was 1.44±0.18% (mean±S.E.M.) for Group I versus 3.88±0.81% for Group III (P<0.01) and neutrophils ×103/ml BAL fluid was 1.7±0.2 versus 7.2±1.7 for Group I versus Group III, respectively (P<0.01). Similarly, interleukin-8 (IL-8) (8.5±1.7 vs 36.8±9.4 pg/ml, P<0.01) and neutrophil elastase (NE) complexed to α1-antiprotease (1.2±0.1 vs 16.6±7.1 ng/ml, P<0.02) were significantly elevated in the oldest versus youngest age group, although α1-antiprotease (582±86 vs 1178±148 ng/ml, P<0.01) and elastase inhibitory capacity (EIC) (8.1±1.3 vs 17.7±1.9 μmol/ml, P<0.01) were also significantly increased in the oldest age group. This cross-sectional investigation suggests that low-grade inflammation exists in the air spaces of many clinically normal, older individuals.

Introduction

Various alterations in lung structure and function have been associated with advancing age. Decreased mucociliary clearance (Goodman et al., 1978), dilatation of airspaces (Ryan et al., 1965), loss of elastic recoil simulating emphysema (Turner et al., 1968, Knudson et al., 1977), loss of elastin fibers (Pierce and Hocott, 1960, Knudson et al., 1977), diminished diffusion capacity (Teculescu and Stanescu, 1970, Crapo and Morris, 1981), diminished PaO2 and increased D(A-a)O2 (Sorbini et al., 1968) and low-grade lower respiratory tract inflammation (Thompson et al., 1992, Meyer et al., 1996), have all been observed in individuals ≥50 years of age. Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) progressively decrease whereas closing volume, residual volume (RV) and functional residual capacity (FRC) increase (Anthonisen, 1986). These changes, some of which appear to progress with age, could compromise lung function in an aging individual as the lung becomes more fragile and less resilient in the face of respiratory and systemic diseases. Age-associated pulmonary dysfunction may diminish quality of life, but, more importantly, impaired lung function may increase the risk of mortality for elderly individuals when beset with an acute pulmonary disease such as pneumonia.

Tissue injury is predominantly mediated by immune cell-derived proteases and oxidants which can act synergistically (Weiss, 1989, Sibille and Reynolds, 1990). Phagocytic cells arrive at areas of tissue inflammation via adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), which is a ligand for the CD18 integrins (LFA-1 and Mac-1) expressed by neutrophils and monocytes (Adams and Shaw, 1994). ICAM-1 is involved in both adhesion and subsequent migration of circulating neutrophils and monocytes into inflamed tissues. Upon activation, neutrophils and macrophages can release numerous proteases (e.g. neutrophil elastase (NE), cathepsin G) and oxidants (e.g. superoxide anion and other oxyradicals generated by membrane NADPH-oxidoreductase or nitric oxide produced via nitric oxide synthase), or oxidant-generating enzymes (e.g. myeloperoxidase, which catalyzes formation of the reactive oxygen intermediate, hypochlorous acid), all of which are important in host defense but also capable of damaging tissues (Weiss, 1989, Sibille and Reynolds, 1990). Unopposed NE has been described as an ‘omnivorous’ enzyme, which can degrade a broad spectrum of peptide substrates, most notably elastin (Adams and Shaw, 1994). Other neutrophil- or monocyte/macrophage-derived degradative enzymes can also degrade and alter extracellular lung matrix (Sibille and Reynolds, 1990, Shapiro, 1994).

Because sustained, low-grade inflammation with increased protease and oxyradical stress may provide a mechanism of elastin loss in normal, aging individuals, we performed bronchoscopy and bronchoalveolar lavage (BAL) in various clinically healthy individuals from discontinuous age groups to determine whether neutrophils are increased in individuals who are relatively advanced in age. We quantitated total cell counts and differential counts. In addition, we measured total immunoreactive α1-antiprotease, NE complexed to α1-antiprotease (NE/α1-antiprotease complex), interleukin-6 (IL-6), interleukin-8 (IL-8) and ICAM-1 in BAL fluid. Serum levels of α1-antiprotease, plasma NE/α1-antiprotease complex and BAL elastase inhibitory capacity (EIC) were also determined.

Section snippets

Study population

Volunteers were screened and recruited from the Madison, WI area, when they responded to advertising and met inclusion and exclusion criteria. We performed bronchoscopy with BAL on three groups of normal volunteers stratified according to age (Group I, 19–36 years, n=30; Group II, 45–55 years, n=11; Group III, 64–83 years, n=26). All subjects had never smoked tobacco or other substances, were physically active and in excellent health and gave no history to suggest gastroesophageal reflux.

Results

Demographic data and spirometric testing results for the three age groups are given in Table 1. Pulmonary function testing was within the range of normal, age-corrected predicted values for all subjects. Potential subjects, who had age-corrected values for FEV1 or FVC which were <80% of the predicted values were excluded from study participation.

No significant complications occurred as a result of bronchoscopy and BAL and the protocol was identical to that utilized by The BAL Cooperative Group

Discussion

We found that the oldest group of clinically healthy, never-smoked individuals had an increased mean neutrophil concentration in BAL fluid when compared to the youngest and intermediate groups. Additionally, significantly increased levels of the potent neutrophil chemoattractant, IL-8 and the neutrophil granular constituent, NE, were present in BAL fluid for the oldest age group. Total protein and α1-antiprotease levels were also increased in BAL, as was EIC. However, although the oldest age

Acknowledgements

Supported by the American Lung Association of Wisconsin and the American Federation for Aging Research.

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