Christopher P. Nielson

Impaired Bronchodilator Response to Albuterol in Healthy Elderly Men and Women

BACKGROUND Lymphocytes of normal elderly subjects and young asthmatics display dysfunctional beta-adrenoceptors. If beta-adrenoceptor dysfunction were found in senescent airways, it might help explain the pathogenesis of late onset asthma. METHODS The bronchodilatory effects of albuterol after methacholine-provoked bronchoconstriction were compared in 17 healthy young (age 20 to 36 years) and 17 healthy elderly (age 60 to 76 years) volunteer subjects. Albuterol was inhaled via dosimeter (initially 7.8 micrograms, doubling every 7.5 min) with forced expiratory flow at 50% vital capacity (FEF50) measured prior to each dose. Albuterol sensitivity was expressed as the cumulative logarithm of the area under the FEF50 recovery curve (AUC); a greater AUC meant lower sensitivity. On another study day, spontaneous recovery from methacholine was assessed similarly. RESULTS There was no intergroup difference in spontaneous recovery. Despite lower methacholine doses provoking similar (35%) FEF50 falls in elderly subjects, albuterol AUC was greater in elderly subjects (6,552%.min.microgram) than young subjects (3,922%.min microgram; p = 0.03). Multiple regression showed that AUC and age were related (p = 0.02). CONCLUSION Airway beta 2-adrenoceptor responsiveness is diminished in old age, suggesting that airway beta-adrenoceptor dysfunction may be implicated in late-onset asthma.

CD40 is functionally expressed on human breast carcinomas: Variable inducibility by cytokines and enhancement of Fas-mediated apoptosis

The CD40 molecule, a member of the TNF receptor gene family, has been intensively studied with respect to regulation of B cell proliferation and survival. Although CD40 is also expressed on carcinoma cell lines, information concerning the biological function of CD40 on cells of epithelial origin is limited. In this study we detected constitutive CD40 on human breast carcinoma cell lines and an increase in CD40 expression following treatment with cytokines IL-1α and IFN-γ. CD40 ligation was also found to increase MHC II expression in cells pretreated with IFN-γ. In contrast to normal B cells, where CD40 signaling provides a potent survival signal, we observed that CD40 ligation in breast carcinoma cells results in growth inhibition and enhanced susceptibility to Fas-mediated apoptosis. Enhanced apoptosis appears to be attributable, at least in part, to an up-regulation of Fas expression caused by CD40 ligation. These results suggest a potentially important role for CD40 in breast tumor biology.

Therapeutic concentrations of theophylline and enprofylline potentiate catecholamine effects and inhibit leukocyte activation

Methylxanthines are primary agents used in treatment of hypersensitivity disease. Because polymorphonuclear leukocyte (PMN) activation is associated with generation of potent inflammatory mediators, xanthine effects on the PMN respiratory burst were studied. Enprofylline, a xanthine with important therapeutic potential, does not antagonize adenosine and was contrasted with theophylline. Although enprofylline was more potent at low concentrations, both drugs exhibited dose-dependent inhibition of PMN activation at concentrations greater than 10 mumol/L (1.8 micrograms/ml). Oxygen metabolite generation was decreased by 30% to 40% at therapeutic drug concentrations and by 85% at 1 mmol/L of theophylline. Inhibition by isoproterenol or prostaglandin E2 but not dibutyryl cAMP was potentiated by either xanthine. Isoproterenol effects were also increased when isoproterenol was evaluated in whole blood specimens obtained from subjects after a loading dose of aminophylline. Although these results were most compatible with cAMP phosphodiesterase inhibition, other commonly proposed mechanisms of methylxanthine activity were also studied. Theophylline but not enprofylline blocked adenosine inhibition of PMN activation. Neither xanthine shifted the calcium dose-response when PMNs were activated with calcium ionophore. Because oxygen metabolites generated by the FMN are mediators of inflammation and hypersensitivity, direct inhibition of PMN activation as well as potentiation of catecholamine activity may be important therapeutic effects of theophylline and enprofylline.

Effects of adenosine on polymorphonuclear leucocyte function, cyclic 3': 5'-adenosine monophosphate, and intracellular calcium.

1 Inhibition of human polymorphonuclear leucocyte (PMN) function by adenosine was studied with respect to effects of adenosine on intracellular cyclic AMP and calcium during the PMN respiratory burst. 2 The adenosine analogue 5′‐N‐ethylcarboxamide‐adenosine (NECA) and L‐N6‐phenyl‐isopropyladenosine (L‐PIA) inhibited PMN oxygen metabolite generation with relative potencies (NECA > adenosine > L‐PIA) characteristic of an A2 receptor. 3 The respiratory burst was inhibited by adenosine when PMN were activated by calcium ionophore or chemotactic peptide but not when cells where activated by oleoyl‐acetyl‐glycerol (OAG). 4 Adenosine increased intracellular cyclic AMP during the PMN respiratory burst regardless of whether cells were stimulated by ionophore, chemotactic peptide or OAG. 5 To determine whether the differences in cell inhibition by adenosine were related to differences in intracellular calcium mobilization by each activating agent, calcium was evaluated with the fluorescent probe, indo‐1. Adenosine suppressed the increase in intracellular calcium following PMN activation by calcium ionophore or chemotactic peptide. In contrast, calcium did not increase in PMN activated by OAG and adenosine did not affect intracellular calcium changes following this stimulus. 6 These results demonstrate that physiological concentrations of adenosine inhibit the PMN respiratory burst in association with an increase in intracellular cyclic AMP and reduction of intracellular calcium.

Glucocorticoid-mediated inhibition of RANTES expression in human T lymphocytes

The chemokine RANTES has been implicated in the pathogenesis of allergic inflammatory diseases including asthma and rhinitis which are frequently treated with glucocorticoids. We observed that dexamethasone dramatically inhibited RANTES mRNA expression dose dependently in anti‐CD3 activated Hut‐78 T cells and human PBMCs. Inhibition of RANTES expression did not appear to be secondary to IL‐2 inhibition and required binding to the intracellular glucocorticoid receptor. The down‐regulation of RANTES expression by glucocorticoids in T cells may directly contribute to the efficacy of these agents in suppressing cellular infiltration and to their anti‐inflammatory properties.

Hemoglobin levels and coronary artery disease

BACKGROUND Anemia is a risk factor for adverse cardiovascular disease outcomes. However, there is limited information concerning the association of hemoglobin concentration and new onset of clinically recognized coronary artery disease (CAD). METHODS An historical cohort study was conducted with patients from Veterans Affairs medical centers. Baseline hemoglobin determinations were evaluated with respect to CAD using data from records of 25,622 subjects with no known heart disease. Coronary artery disease was identified from a new diagnosis based on the International Classification of Diseases, Ninth Edition, coding or a new prescription for nitroglycerin. Models were adjusted for age, sex, body mass index, smoking, systolic blood pressure, diastolic blood pressure, fasting glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, creatinine clearance, and use of statin or beta-blocker. RESULTS Among the cohort, 5297 (20.7%) subjects developed CAD over 73,895 person-years of follow-up. Compared with control hemoglobin levels of 15.0 to 17.0 g/dL, the multivariable-adjusted risk of CAD increased with lower hemoglobin levels: an adjusted hazard ratio (HR) of 1.47 and 95% confidence interval (CI) of 1.18 to 1.84 for hemoglobin levels of 9.0 to 11.0 g/dL; an HR of 1.34 and 95% CI of 1.20 to 1.49 for 11.0 to 13.0 g/dL; and an HR of 1.07 and 95% CI of 1.01 to 1.13 for 13.0 to 15.0 g/dL. Hemoglobin levels > or = 17.0 g/dL were also associated with increased risk for CAD (adjusted HR 1.22, 95% CI 1.08-1.37). CONCLUSIONS Hemoglobin levels > or = 17 or < 15 g/dL are independently associated with increase risk for new cardiac events.

Impaired beta-adrenoceptor function, increased leukocyte respiratory burst, and bronchial hyperresponsiveness☆

Inflammatory processes have potential importance in the pathogenesis of bronchial hyperresponsiveness and asthma. Because beta-adrenoceptor function may be impaired in asthma, we studied regulation of the leukocyte respiratory burst using blood samples from subjects with bronchial hyperresponsiveness to methacholine. Leukocytes from hyperresponsive subjects were less responsive to the beta-agonist isoproterenol than were leukocytes from healthy control subjects. The magnitude of the respiratory burst was increased in cells from hyperresponsive subjects and correlated with the degree of methacholine responsiveness. These results demonstrate that peripheral leukocytes reflect a functional impairment in beta-adrenergic responsiveness that parallels airway hyperresponsiveness. Because untreated subjects demonstrated a reduction in beta-adrenergic response, the impairment in beta-adrenoceptor function was not a result of drug therapy and may be associated with the pathogenesis of asthma.

β‐Adrenoceptor‐mediated modulation of calcium ionophore activated polymorphonuclear leucocytes

1 β‐Adrenoceptor‐mediated modulation of calcium‐mediated stimulus‐response coupling was studied using calcium ionophore (A23187) activation of polymorphonuclear leucocytes (PMNL). Oxygen metabolite generation was measured with luminol‐ and lucigenin‐dependent chemiluminescence in both whole blood and isolated PMNL. 2 Isoprenaline reduced PMNL response by 53% in a dose‐dependent fashion. The effect was saturable, stereoselective, antagonized by propranolol and significant at isoprenaline concentrations as low as 0.01 nM. Fifty % maximal response was induced by 0.26 nM, 3 nM, and 125 nM isoprenaline, adrenaline and noradrenaline respectively. 3 Because the effects of β‐adrenoceptor agonists in PMNL have not consistently correlated with measurements of cyclic AMP, alternative means of increasing cyclic AMP were studied. Forskolin and dibutyryl cyclic AMP inhibited PMNL with significant effects at 1.0 μM and 10 μM respectively. 4 The effects of β‐adrenoceptor agonists were much greater when PMNL were activated by calcium ionophore compared with opsonized zymosan. Isoprenaline had no effect upon l‐oleoyl‐2‐acetylglycerol activated PMNL. 5 Because catecholamine modulation of oxygen metabolite generation can be characterized pharmacologically, PMNL activation by calcium ionophore is an excellent model for study of β‐adrenoceptor function in viable human cells. 6 In contrast to previously described β‐adrenoceptor agonist modulation of PMNL function, inhibition of calcium‐mediated activation is significant at physiological concentrations. The clinical consequences of such catecholamine effects are dependent upon the mechanism of PMNL activation in a specific circumstance.

Divergence in NK cell and cyclic AMP regulation of T cell CD40L expression in asthmatic subjects

T cells are central in the pathogenesis of asthma, and the associated ligand, CD40L, plays an important role by increasing production of immunoglobulin E and inflammatory mediators. β‐Adrenoceptor agonists are commonly used in asthma, although little is known regarding effects on CD40L expression and T cell activation. Here, we demonstrate that cyclic adenosine monophosphate (cAMP) and β‐adrenoceptor agonists differentially regulate CD40L in asthma. cAMP increased naïve T cell CD40L expression in asthmatics (9.8±8.5 increase in percent CD40L‐positive cells), and expression in control subjects was inhibited (7.1±6.0 decrease in percent CD40L‐positive cells; P< 0.05). Cell depletion and reconstitution experiments were used to determine that cAMP enhancement of CD40L required cell‐to‐cell contact with an asthma‐associated natural killer (NK) cell subset. The NK cell subset expressed elevated levels of CD95, and in vitro‐generated CD95+ NK2 cells also produced similar effects on CD40L expression. Our findings suggest that a subset of NK cells with elevated CD95 expression is associated with asthma and can reverse cAMP inhibitory effects on T cell CD40L with the potential to increase disease exacerbation.

Intensive care and invasive ventilation in the elderly patient, implications of chronic lung disease and comorbidities.

Aims: Elderly patients have an increasing prevalence of illness that requires consideration of critical care and invasive ventilatory support. Although critical care of even the very elderly can provide value, with increasing age the potential risks of treatment and diminishing returns with respect to quality and quantity of life result in a need for careful evaluation. Variable combinations of impaired organ function, active disease and residual pathology from past disease and injury all affect critical care, with the consequence that the elderly are a very heterogeneous population. Recognizing that critical care is a limited resource, it is important to identify patients who may be at increased risk or least likely to benefit from treatment. Patients with functional impairments, nutritional deficiencies and multiple comorbidities may be at highest risk of poor outcomes. Those with very severe disease, extreme age and requirements for prolonged ventilatory support have high in-hospital mortality. Functional impairments, comorbidities and severity of illness are usually more important considerations than chronologic age. The objective of this review is to identify how common problems of the elderly affect critical care and decisions concerning use of invasive ventilatory support.