Lung Aging Research Articles

Does lung aging have an impact on chronic obstructive pulmonary disease?

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory airway disease. It has become one of the commonest diseases worldwide and a major global healthcare problem. The disease progresses very slowly and, in contrast to asthma, the majority of affected patients are middle-aged or elderly. There is increasing evidence of a direct relationship between aging and an increased incidence of chronic inflammatory disease. Thus, in this review, the link between aging of the lung and the progression of COPD is discussed. Aging, or senescence, is defined as the progressive decline in homeostasis that occurs after the reproductive phase of life is completed, leading to an increasing risk of disease or death. This is the result of a failure of organ maintenance resulting from DNA damage, oxidative stress and telomere shortening. During aging, pulmonary function progressively deteriorates and inflammation of the lung increases, and these changes are accompanied by structural changes. Environmental stimul...

Animal models of pulmonary emphysema: a stereologist's perspective

A variety of animal models have been suggested as models of pulmonary emphysema; these are critically discussed in the present article from a stereologist9s perspective. In addition, a stereological design for the quantification of experimentally induced emphysema is proposed. On the basis of the widely accepted definition of pulmonary emphysema being an “abnormal permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of their walls,” quantitative morphology is the only method with which to reliably assess the presence of emphysema. Recognising this, careful inspection of animal models that are based on instillation of elastase, genetic alterations, inhalation of cigarette smoke or induction of apoptosis, reveals that both criteria of emphysema definition were demonstrated in surprisingly few of them. Several aspects are suggested to be critical for the understanding of animal models of human emphysema. For example, genetic models that rely on the inhibition of the formation of alveoli during post-natal alveolarisation should clearly be distinguished from models that rely on the loss of mature alveoli after alveolarisation is complete. Furthermore, inhalation models that are characterised by exposed animals exhibiting a severe loss of body weight should carefully examine the relative contribution of intervention and weight loss, respectively. Models that rely on the exposure of juvenile animals for several weeks or even months should take into account the effects of normal lung growth and ageing. Stereology offers appropriate tools with which to quantify the parameters relevant to assess development and the regeneration of emphysema. Stereologists continue to develop tools that will help ascertain the reliability of established and new models. If inappropriate parameters continue to be used for the evaluation of animal models of emphysema, thinking and resources are likely to be misdirected and the models may limit rather than expand the understanding of human emphysema and the development of new therapies.

23 An attempt to correlate ‘comprehensive geriatric assessment’ (CGA), treatment assignment and clinical outcome in elderly cancer patients: preliminary results of a phase II open study

The aim of this study was to determine the impact of patient selection based on age, comorbidity and performance status on the efficacy of platinum-free combination therapy on non-small-cell lung cancer after 65 years of age.We analyzed the overall response rate, the median survival time, the 1-year survival rate, toxicity and quality of life after one to three 6-week cycles of docetaxel 30 mg/m2 weekly and gemcitabine 900 mg/m2 at weeks 1, 2, 4 and 5. Fifty patients (median age 73.7 years) were eligible. The mean number of comorbid conditions per patient was 0.8 [Balducci L. Lung cancer and aging. ASCO 2005. Educational book. p. 587–91; Piquet J, Blanchon F, Grivaux M, et al. Primary bronchial carcinoma in elderly subjects in France. Rev Mal Respir 2003;20:691–9; Jatoi A, Hillman S, Stella P, et al. Should elderly non-small-cell lung cancer patients be offered elderly-specific trials? Results of a pooled analysis from the North Central Cancer Treatment Group. J Clin Oncol 2005;23:9113–9; Balducci L, Extermann M. Management of cancer in the older person: a practical approach. Oncologist 2000;5:224–37]. Forty-five patients were assessable: 17 (34%) had an objective response, 18 (36%) had stable disease and 10 progressed (20%). The median survival time was 7 months and the 1-year survival rate 23.5%. The main grade III–IV adverse event was neutropenia (32% of patients).Platinum-free dual-agent chemotherapy gives similar results in patients over 65, selected on the basis of their precise age and comorbidity, to that reported in younger subjects.

22 Feasibility of minimal geriatric assessment of elderly lung cancer patients treated in an oncology out-patient setting

The aim of this study was to determine the impact of patient selection based on age, comorbidity and performance status on the efficacy of platinum-free combination therapy on non-small-cell lung cancer after 65 years of age.We analyzed the overall response rate, the median survival time, the 1-year survival rate, toxicity and quality of life after one to three 6-week cycles of docetaxel 30 mg/m2 weekly and gemcitabine 900 mg/m2 at weeks 1, 2, 4 and 5. Fifty patients (median age 73.7 years) were eligible. The mean number of comorbid conditions per patient was 0.8 [Balducci L. Lung cancer and aging. ASCO 2005. Educational book. p. 587–91; Piquet J, Blanchon F, Grivaux M, et al. Primary bronchial carcinoma in elderly subjects in France. Rev Mal Respir 2003;20:691–9; Jatoi A, Hillman S, Stella P, et al. Should elderly non-small-cell lung cancer patients be offered elderly-specific trials? Results of a pooled analysis from the North Central Cancer Treatment Group. J Clin Oncol 2005;23:9113–9; Balducci L, Extermann M. Management of cancer in the older person: a practical approach. Oncologist 2000;5:224–37]. Forty-five patients were assessable: 17 (34%) had an objective response, 18 (36%) had stable disease and 10 progressed (20%). The median survival time was 7 months and the 1-year survival rate 23.5%. The main grade III–IV adverse event was neutropenia (32% of patients).Platinum-free dual-agent chemotherapy gives similar results in patients over 65, selected on the basis of their precise age and comorbidity, to that reported in younger subjects.

Tomato juice prevents senescence-accelerated mouse P1 strain from developing emphysema induced by chronic exposure to tobacco smoke

The senescence-accelerated mouse (SAM) is a naturally occurring animal model for accelerated aging after normal development and maturation. SAMP1 strain was reported to show age-related structural and functional changes in lung and to be a murine model of senile lung. We postulated that aging of lung is an important intrinsic process for development of emphysema and even in a short period of tobacco smoke exposure may be able to generate emphysema. At age 12 wk, SAMP1 inhaled air or 1.5% tobacco smoke (total particulate matter 23.9 mg/m3) through the nose for 30 min/day, 5 days/wk, and for 8 wk. The mean linear intercepts (MLI) and destructive index (DI) of lung were significantly increased [air vs. smoke (means+/-SE); MLI, 68.76+/-0.69 vs. 75.34+/-1.70 microm, P<0.05 and DI, 8.61+/-0.38 vs. 16.18+/-1.54%, P<0.05], whereas no significant changes were observed in SAMR1, control mice that show normal aging. In contrast, smoke-induced emphysema was completely prevented by concomitant ingestion of lycopene given as tomato juice [MLI: smoke with/without lycopene (mean+/-SE), 62.87+/-0.8 vs. 66.90+/-1.33 microm, P<0.05]. Smoke exposure increased apoptosis and active caspase-3 of airway and alveolar septal cells and reduced VEGF in lung tissues, but tomato juice ingestion significantly reduced apoptosis and increased tissue VEGF level. We conclude that SAMP1 is a useful model for tobacco smoke-induced emphysema and a valuable tool to explore both pathophysiological mechanisms and the effect of therapeutic intervention on smoke-induced emphysema.

Early developmental origins of impaired lung structure and function

Epidemiological studies show that exposure to factors that restrict fetal growth or lead to low birthweight can alter lung development and have later adverse effects on lung function and respiratory health. The major causal factors include reduced nutrient and oxygen availability, nicotine exposure via maternal tobacco smoking and preterm birth, each of which can affect critical stages of lung development. Experimental studies show that these environmental insults can permanently alter lung structure and hence lung function, increasing the risk of respiratory illness and accelerating the rate of lung aging. Further studies are required that address the molecular and cellular mechanisms by which these factors adversely affect lung development and whether such effects can be blocked or reversed. Ultimately however, a major goal should be to prevent prenatal compromises through clinical monitoring, and in the case of smoking through education, thereby ensuring that each fetus has the best possible environment in which to develop.

Fetal growth restriction has long-term effects on postnatal lung structure in sheep.

We have previously shown that fetal growth restriction (FGR) during late gestation in sheep affects lung development in the near-term fetus and at 8 wk after birth. In the present study, our aim was to determine the effects of FGR on the structure of the lungs at 2 y after birth; our hypothesis was that changes observed at 8 wk after birth would persist until maturity. FGR was induced in sheep by umbilicoplacental embolization, which was maintained from 120 d until delivery at term (approximately 147 d); birth weights of FGR lambs were 41% lower than in controls. At 2 y after birth, body and lung weights were not different, but there were 28% fewer alveoli and alveoli were significantly larger than in controls; hence there was a 10% reduction in the internal surface area relative to lung volume in FGR sheep compared with controls. The lungs of FGR sheep, compared with controls, had thicker interalveolar septa as a result of increased extracellular matrix deposition; the alveolar blood-air barrier was also thicker, largely because of an 82% increase in basement membrane thickness. These changes are qualitatively similar to those observed at 8 wk. Our data show that structural alterations in the lungs induced by FGR that were apparent at 8 wk were still evident at 2 y after birth, indicating that FGR may result in permanent changes in the structure of the lungs of the offspring and may affect respiratory health and lung aging later in life.

Novel drug delivery systems for insulin: clinical potential for use in the elderly.

Diabetes mellitus is a very common disease in the elderly and its complications are responsible for excess morbidity/mortality, loss of independence and impaired quality of life. Recent studies, while not performed in the elderly, have outlined the importance of achieving tight glycaemic control in order to prevent complications. Eighty years after its discovery, subcutaneous insulin remains a major treatment for diabetes. It is used as a first-line agent in type 1 diabetes, and in type 2 diabetes when oral antihyperglycaemic agents combined with diet and exercise fail to achieve an appropriate metabolic control. To avoid injections, other routes of insulin administration have been studied, including oral, dermal and rectal routes but they were not found to be appropriate for clinical use. Buccal or nasal insulin combined with absorption enhancers proved to have interesting properties. Inhaled insulin appears to be suitable for use in patients with diabetes because of its better bioavailability and a pharmacokinetic profile that mimics the time kinetics of insulin secretion after a meal. Clinical studies were conducted among small numbers of patients with type 1 or type 2 diabetes who had been treated with subcutaneous insulin. Inhaled insulin was given three times daily, just before meals, and was combined with a bedtime subcutaneous injection of long-acting insulin. In patients with type 1 or type 2 diabetes the metabolic control achieved with inhaled insulin was similar to that obtained with a subcutaneous insulin regimen. Tolerance of inhaled insulin was good and treatment satisfaction was better than that with the subcutaneous regimen. Insulin inhalation appears to be an interesting way of insulin delivery for elderly patients with diabetes. However, no studies have been conducted in elderly patients with diabetes to assess this route's acceptability, convenience and ease of use in this particular population. In addition, it is necessary to conduct pharmacokinetic studies in the elderly because lung aging might reduce the bioavailability of inhaled insulin.

Patterns of Lung Function in Asymptomatic Nonsmoking Men and Women in the People's Republic of China

PURPOSE: To evaluate patterns of lung function in healthy, working Chinese men and women in different geographic areas of the People's Republic of China (PRC). METHODS: We conducted lung function tests on 2926 asymptomatic, never smoking Chinese men and women aged 35–56 years residing in or around Beijing and Guangzhou. Within each of these locations, separate urban and rural samples were recruited. RESULTS: Age and height adjusted lung function was greater in Beijing than in Guangzhou, and within each city for residents of rural vs. urban areas. Among women, estimated rates of lung aging were greater in Beijing than in Guangzhou, and in urban vs. rural areas. Both FEV 1 and FVC exhibited a curvilinear association with body mass index. CONCLUSIONS: Lung function data from this largely working cohort exhibited marked geographic and urban-rural differences in this never smoking, adult Chinese cohort. Such variation is not uncommon and may reflect differences in body size, diet, and environmental and occupational exposures across these different settings. Caution should be used in applying published reference equations to populations from different parts of the PRC.

Tyrosyl radical production by myeloperoxidase: a phagocyte pathway for lipid peroxidation and dityrosine cross-linking of proteins

To kill invading bacteria, viruses, and fungi, phagocytes secrete hydrogen peroxide (H 2O 2) and the heme enzyme myeloperoxidase. We have explored the possibility that myeloperoxidase might use H 2O 2 to convert L-tyrosine to tyrosyl radical. Activated human neutrophils and monocytes used the system to oxidize free L-tyrosine to o,o′-dityrosine, a stable product of tyrosyl radical. Protein-bound tyrosyl residues exposed to myeloperoxidase, H 2O 2, and l-tyrosine were also oxidized to o,o′-dityrosine. The cross-linking reaction required free L-tyrosine, suggesting that myeloperoxidase converts the amino acid to a diffusible radical catalyst that promotes protein oxidation. We used electron paramagnetic resonance to provide direct evidence that the oxidizing intermediate is free tyrosyl radical. Myeloperoxidase-generated tyrosyl radical also initiates lipid peroxidation, suggesting that activated phagocytes might also be able to oxidize lipids in host tissues. Moreover, myeloperoxidase is present and active in human atherosclerotic tissue, and levels of protein-bound dityrosine are elevated in such lesions. Our recent studies indicate that activated neutrophils use oxidants generated by the phagocyte NADPH oxidase to produce protein-bound dityrosine during acute inflammation. Collectively, these findings suggest that generation of tyrosyl radical by myeloperoxidase allows activated phagocytes to damage both proteins and lipids. Elevated levels of o,o′-dityrosine have been detected in inflammatory lung disease, neurodegenerative disorders, and aging. Thus, oxidation of tyrosine to tyrosyl radical might play a role in the pathogenesis of many diseases.

EC-SOD and the response to inflammatory reactions and aging in mouse lung

The lung is exposed to high oxygen tension and oxygen free radicals have been implicated in many pathologies of the organ. Extracellular superoxide dismutase occurs in high concentration in the lung and protects against hyperoxia-induced inflammation. We hypothesized that the enzyme might ameliorate other types of inflammation as well as aging-related changes of the organ. Tracheal instillation of endotoxin plus zymosan into extracellular superoxide dismutase knockout and wild-type mice resulted in a marked neutrophilic inflammation and increases in inflammatory cytokines, protein, and lactate dehydrogenase activity in the bronchoalveolar lavage fluid. There were no significant differences between the genotypes. Repeated challenges with ovalbumin caused an allergic inflammation with increases in eosinophils, interleukin-5, protein, and lactate dehydrogenase activity in the bronchoalveolar lavage fluid. Only minimal differences between the genotypes were found. In lungs from 2-year-old mice, marginal increases in inflammatory variables and fibrosis were found in the knockout mice. In conclusion, extracellular superoxide dismutase had a negligible role in the present inflammation and allergy models and for the long-term integrity of the organ.

Oxidative stress, antioxidant status, and the contracting diaphragm.

Reactive oxygen species, including free radicals, are produced through a number of biochemical reactions, often as a consequence of aerobic metabolism. A system of antioxidant enzymes and scavenger substrates provides protection of membrane lipids, proteins, and DNA. An imbalance between production of reactive oxygen species and antioxidant protection results in "oxidative stress." Oxidative stress is believed to contribute to numerous pathological conditions including atherosclerosis, obstructive lung disease, aging, and fatigue of skeletal muscles including the diaphragm. Strenuous exercise, inflammation, infection, obstructive lung diseases, etc. increase exposure of the diaphragm to reactive oxygen species. Emerging data indicate that reactive oxygen species alter diaphragm contractions primarily in response to low-frequency stimulation. The response of the diaphragm is profoundly influenced by the degree of oxidative stress, fatigue state, glutathione status, and age. Exercise training results in an upregulation of antioxidant enzyme activities in the diaphragm and thus could provide additional protection against oxidative stress.

Time courses of LPS-induced cytokine and transcription factor expression in rats and the inhibitory effect by phenyl n- tert-butyl nitrone

To kill invading bacteria, viruses, and fungi, phagocytes secrete hydrogen peroxide (H2O2) and the heme enzyme myeloperoxidase. We have explored the possibility that myeloperoxidase might use H2O2 to convert L-tyrosine to tyrosyl radical. Activated human neutrophils and monocytes used the system to oxidize free L-tyrosine to o,o′-dityrosine, a stable product of tyrosyl radical. Protein-bound tyrosyl residues exposed to myeloperoxidase, H2O2, and l-tyrosine were also oxidized to o,o′-dityrosine. The cross-linking reaction required free L-tyrosine, suggesting that myeloperoxidase converts the amino acid to a diffusible radical catalyst that promotes protein oxidation. We used electron paramagnetic resonance to provide direct evidence that the oxidizing intermediate is free tyrosyl radical. Myeloperoxidase-generated tyrosyl radical also initiates lipid peroxidation, suggesting that activated phagocytes might also be able to oxidize lipids in host tissues. Moreover, myeloperoxidase is present and active in human atherosclerotic tissue, and levels of protein-bound dityrosine are elevated in such lesions. Our recent studies indicate that activated neutrophils use oxidants generated by the phagocyte NADPH oxidase to produce protein-bound dityrosine during acute inflammation. Collectively, these findings suggest that generation of tyrosyl radical by myeloperoxidase allows activated phagocytes to damage both proteins and lipids. Elevated levels of o,o′-dityrosine have been detected in inflammatory lung disease, neurodegenerative disorders, and aging. Thus, oxidation of tyrosine to tyrosyl radical might play a role in the pathogenesis of many diseases.

Introduction to working group on tropospheric ozone, Health Effects Institute environmental epidemiology planning project.

The working group on tropospheric ozone of the Health Effects Institute has evaluated the need for epidemiologic studies on the health effects of ozone (O3) exposure. This paper summarizes current data and identifies possible research questions. The extent to which ozone exposure results in chronic health effects is largely undefined and is the central issue for epidemiologic studies. Most current data focus on transient endpoints; the link between acute changes in symptoms and/or lung function and possible chronic effects has not been established. Concepts of ozone-induced health effects have been extended to include processes of chronic disease (e.g., markers of ongoing inflammation and repair, markers of accelerated lung aging). Traditional epidemiologic studies performed have focused only on accelerated lung aging and are limited by a number of methodologic problems. Recent, very preliminary, studies suggest new opportunities for the use of human lung tissue and a variety biological response markers as part of epidemiologic studies. The identification of sensitive subpopulations with regard to ozone-induced health effects has been studied incompletely and is important both in terms of study efficiency and mechanistic insight. Methodologic advances in the reconstruction of past ozone exposure are seen as essential, as is the incorporation of emerging markers of biologic response to ozone into traditional epidemiologic study designs. Finally, more data on the joint and independent contribution of other ambient air pollutants to putative ozone-induced health effects is warranted.

Fructose 2,6-bisphosphate: Changes during neonatal maturation and aging of rat and potential role in regulation of glucose utilization

During the 6 days following birth, tissue levels of fructose-2,6-P 2 in rat brain, liver, muscle, heart and kidney did not significantly change. However, by the tenth day postpartum fructose-2,6-P 2 levels in brain, heart, and skeletal muscle increased approximately 50% and attained adult values. During maturation of liver, adult levels of fructose-2,6-P 2 were not achieved until 3–4 weeks after birth or approximately at the time of maximum rates of gluconeogenesis. Renal fructose-2,6-P 2 levels in the neonate were initially elevated and 2–3 weeks after birth decreased approximately 2.5-fold to adult values. With the exception of the pons-medulla, which showed no significant changes in fructose-2,6-P 2 amounts, levels of this regulatory sugar from aging brain regions were generally decreased. The fructose-2,6-P 2 levels from heart atria of old rats (24–30 month) were also significantly decreased. In diaphragm, the fructose-2,6-P 2 levels were increased at 12 months of age and at 27 months of age were twice the level at 3 months. The fructose-2,6-P 2 levels during the aging of liver, skeletal muscle (EDL and soleus), spleen, thymus, kidney, testis and lung were not significantly altered.

Lung function and aging: the development and decline of lung function in health and disease

Lung function and aging: the development and decline of lung function in health and disease

Aging and lung antioxidant enzymes, glutathione, and the lipid peroxidation in the rat

The five major antioxidants enzymes, cytochrome oxidase (C)X), GSH, and GSSG, and endogenous and in vitro stimulated lipid perozidation (TBS)-RS) were assayed in the lung of old (28 months) and young (9 months) adult rats due to the almost total absence of data of this kind in this tissue, which is normally exposed to relatively high pO 2 throughout life. Catalase, selenium (Se)-dependent GSH peroxidase (GPx), GSH reductase, GSH, GSSG, GSSG/GSH, and in vivo and in vitro TBA-Rs showed similar values in old and young animals. The decrease observed for non Se-dependent GPx disappeared when the values were expressed in relation to COX activity. Only superoxide dismutase showed a clear decrease when referred both to protein and COX activity. These results suggest that lung aging is not accelerated in old age due to a decrease in the antioxidant capacity of the tissue. Nevertheless, they are compatible with a continuous damage of the lung tissue by free radicals throughout the life span.

The regulation of lung elastin synthesis

The important role that elastin plays in the development and proper function of lung has long been recognized. Also, the intimate connection between pulmonary emphysema and the destruction of alveolar elastin has been well established. Understanding the mechanisms regulating pulmonary elastin synthesis is crucial to fully understanding these normal and pathological processes. In this article, we review recent literature on elastin structure, the elastin gene and its multiple RNA transcripts, and the different tropoelastin isoforms that are translated from these mRNAs. The similarity of lung and aortic elastin and the cellular origin of lung elastin are also discussed. We next examine the few studies addressing regulation of elastin expression during lung development, maturation, and aging. The search for modulators of pulmonary elastogenesis, which has yielded mostly negative results, is then reviewed. Finally, we present a cell culture model that has been developed to study the molecular basis of lung injury in pulmonary emphysema.

Neonatal pulmonary oxygen toxicity in the rat and lung changes with aging

The aims of this study were to determine if neonatal hyperoxia exposure causes permanent lung damage and to define the relationship between neonatal lung oxygen toxicity and aging. Sprague-Dawley newborn rats (n = 85) breathed 100% oxygen (O2) or room air (RA) during the first 8 days of life, and then RA. At 2 and 22 months of age we assessed right ventricular (RV) systolic pressure (RVSP), RV weight, saline and air pressure-volume curves, volume density of lung parenchyma and nonparenchyma, parenchymal air space (PAS), mean linear intercept (Lm), number of small arteries/mm2 and the extent of their medial muscularization. Aging in RA did not affect the RVSP, RV weight, the number of small arteries/mm2, or their muscularization. The maximal lung volume/g of dry lung and the elastic recoil pressure between 40 and 90% maximal lung volume decreased. The volume density of lung parenchyma increased but the fraction of the lung parenchyma that was PAS decreased and that of the alveolar septa and Lm increased. The O2-treated rats at 60 days of age had increased RVSP and RV weights with a decrease in the small arteries/mm2. The lung parenchymal volume density and PAS increased and the density of alveolar septa decreased. The Lm increased and the alveoli/mm2 and elastic recoil pressure decreased. The lung damage seen in the O2-treated rats at 60 days persisted and in addition underwent the changes seen in the aging controls. However, the extent of muscularization of the arteries decreased. We conclude that neonatal hyperoxia causes permanent functional and structural changes of the lung but these do not interact with aging; that is, the effects of O2 toxicity and aging are additive but not synergistic.

The use of lung function tests in identifying factors that affect lung growth and aging.

Lung function tests are used both clinically, in assessing disease, and epidemiologically, in identifying those factors which influence the growth and aging process of the lungs. The user must beware of several common pitfalls in the use of these tests, however. First, the commonly used tests of lung function can only identify patterns of dysfunction, not specific pathologic processes. Second, these tests are subject to many sources of intra- and inter-subject variability, making it difficult to dissect out the signal (for example, the rate of lung aging in adults) from the noise which may greatly exceed the signal. Finally, the analysis of longitudinal pulmonary function data is complicated by the alinearity of the growth and aging process, missing data, variable follow-up times, information censoring mechanisms and covariate processes, and problems in defining abnormality.