Use of ICS/LABA (extra-fine and non-extra-fine) in elderly asthmatics.

Age represents an exclusion criterion in randomized clinical trials designed to test the efficacy and safety of inhaled drugs in asthma. As a consequence, data on efficacy and safety of inhaled corticosteroid (ICS) and long-acting ß2 agonist (LABA) combinations in elderly asthmatics are scanty. Older age is associated with an increased proportion of comorbid conditions; in addition, all organ functions undergo a process of senescence, thus reducing their ability to metabolize the agents. Overall, these age-associated conditions may variably, and often unpredictably, affect the metabolism and excretion of respiratory drugs. However, pharmacological treatment of asthma does not follow specific recommendations in the elderly. In the elderly, the ICS/LABA combinations may carry an increased risk of local indesiderable effects, primarily due to the lack of coordination between activation of the device and inhalation, and systemic adverse events, mainly due to the greater amount of active drug that is available because of the age-associated changes in organ functions as well as drug-to-drug and drug-to-concomitant disease interactions. The extra-fine formulations of ICSs/LABAs, which allow for a more favorable drug deposition in the lungs at a reduced dose, may contribute to overcome this issue. This review revises the efficacy and safety of treatment with ICSs/LABAs, focusing on the main pharmacodynamic and pharmacokinetic properties of the drugs and highlighting the potential risks in the elderly asthmatic population.

Asthma in the elderly: a different disease?

KEY POINTS: Asthma in the elderly can be difficult to identify due to modifications of its clinical features and functional characteristics.Several comorbidities are associated with asthma in the elderly, and this association differs from that observed in younger patients.In clinical practice, physicians should treat comorbidities that are correlated with asthma (i.e. rhinitis or gastro-oesophageal reflux), assess comorbidities that may influence asthma outcomes (i.e. depression or cognitive impairment) and try to prevent comorbidities related to -'drug-associated side-effects (i.e. cataracts, arrhythmias or osteoporosis)."Geriatric asthma" should be the preferred term because it implies the comprehensive and multidimensional approach to the disease in the older populations, whereas "asthma in the elderly" is only descriptive of the occurrence of the disease in this age range. EDUCATIONAL AIMS: To present critical issues in performing differential diagnosis of asthma in the elderly.To offer the instrument to implement the management of asthma in the most advanced ages. Asthma is a chronic airway disease that affects all ages, but does this definition also include the elderly? Traditionally, asthma has been considered a disease of younger age, but epidemiological studies and clinical experience support the concept that asthma is as prevalent in older age as it is in the young. With the ever-increasing elderly population worldwide, the detection and proper management of the disease in old age may have a great impact from the public health perspective. Whether asthma in the elderly maintains the same characteristics as in young populations is an interesting matter. The diagnostic process in older individuals with suspected asthma follows the same steps, namely a detailed history supported by clinical examination and laboratory investigations; however, it should be recognised that elderly patients may partially lose reversibility of airway obstruction. The correct interpretation of spirometric curves in the elderly should take into account the physiological changes in the respiratory system. Several factors contribute to delaying the diagnosis of asthma in the elderly, including the age-related impairment in perception of breathlessness. The management of asthma in advanced age is complicated by the comorbidities and polypharmacotherapy, which advocate for a comprehensive approach with a multidimensional assessment. It should be emphasised that older age frequently represents an exclusion criterion for eligibility in clinical trials, and current asthma medications have rarely been tested in elderly asthmatics. Ageing is associated with pharmacokinetic changes of the medications. As a consequence, absorption, distribution, metabolism and excretion of antiasthmatic medications can be variably affected. Similarly, drug-to-drug interactions may reduce the effectiveness of inhaled medications and increase the risk of side-effects. For this reason, we propose the term "geriatric asthma" be preferred to the more generic "asthma in the elderly".

Blood eosinophils and treatment response in hospitalized exacerbations of chronic obstructive pulmonary disease: A case-control study.

BACKGROUND: In outpatients with chronic obstructive pulmonary disease (COPD), blood eosinophilia is considered as a biomarker of response to systemic corticosteroid therapy. However, little is known on whether blood eosinophilia is also predictive of positive clinical outcome in severe acute exacerbations of COPD requiring hospitalization. We hypothesized that blood eosinophil-positive severe acute exacerbations of COPD differ from eosinophil-negative ones in terms of response to therapy and clinical outcomes. METHODS: To test our experimental hypothesis, we retrospectively analyzed medical records of patients with COPD admitted to our ward because of severe exacerbation, over a two-year period of observation. After evaluation of inclusion and exclusion criteria, 132 patients were selected and divided in cases (blood eosinophilia ≥2% at admission; n = 20) and controls (blood eosinophilia <2% at admission; n = 112). RESULTS: Cases had a shorter hospital stay than controls (geometric mean = 8.9 ± 1.5 versus 11.3 ± 1.5 days; p = 0.028). In addition, cases had a significantly lower consumption of systemic corticosteroids (geometric mean = 19.2 ± 4.0 versus 35.7 ± 2.5 mg per day of hospitalization; p = 0.012). CONCLUSIONS: In severe acute exacerbations of COPD requiring hospitalization, blood eosinophilia identifies a subgroup of subjects characterized by a prompt response to treatment with shorter hospital stay.

Challenges in the pharmacological treatment of geriatric asthma.

Asthma in older populations is characterized by frequent comorbid conditions, which increase the risk of side effects and of detrimental interactions between respiratory and non-respiratory drugs. These observations lead to the need to manage asthma in older populations by applying a multidimensional assessment and a multidisciplinary treatment; therefore, we favor the use of the 'geriatric' term to define asthma in the elderly. Geriatric asthma is a complex disease, which may not necessarily imply that it is also complicated, although the two conditions may often coexist. On this basis, the switch from an organ-driven management to the holistic approach may be the key factor to attain optimal control of the disease in this age range. The current review discusses the age-related factors affecting asthma treatment in the oldest individuals, such as the comorbid conditions, and age-related changes of metabolism and excretion that can impair the efficacy and safety of drugs.

A mild form of rituximab-associated lung injury in two adolescents treated for nephrotic syndrome.

Rituximab is used as a steroid/calcineurin inhibitor-saving agent in patients with nephrotic syndrome. Safety is a crucial issue for justifying widespread use of the drug in this clinical setting. Rituximab-associated lung injury (RALI) is a severe and potentially life-threatening complication in oncohaematological and rheumatological patients, while it has only been anecdotally reported in association with idiopathic nephrotic syndrome (2 cases described, 1 with fatal outcome). We describe a benign form of RALI occurring in two adolescents treated with rituximab (single pulse of 375 mg/m(2)) for nephrotic syndrome. Before treatment, the patients were in good clinical condition while receiving a combination of steroids and calcineurin inhibitors (tacrolimus, case 1 and cyclosporine, case 2). The two patients developed full blown RALI (ie, ground-glass lesions on CT, negative bronchoscopy with bronchoalveolar lavage and deficit in diffusion lung CO transfer), 14 and 40 days after rituximab infusion, respectively. Recovery was rapid and complete after administering steroids in case 1 and with no therapy in case 2. We conclude that RALI may occur in stable non-immunocompromised patients with nephrotic syndrome and its frequency may be higher than expected. Clinical presentation may be mild and resolve after steroids, suggesting hypersensitivity as the main mechanism. Rapid recognition and prompt steroid therapy, if needed, are mandatory for resolution.

Erratum to: Safety Considerations of Inhaled Corticosteroids in the Elderly.

Inhaled corticosteroids (ICSs) are widely used in the treatment of patients with chronic obstructive pulmonary diseases. However, high-dose regimens and long-term use of ICSs have the potential to cause a variety of local and systemic side effects such as candidiasis, cataracts, glaucoma, and osteoporosis. The use of ICSs can also be associated with the risk of bone fractures, diabetes mellitus and pneumonia. These ICS-related side effects are of particular importance in elderly patients due to the presence of comorbidities and age-related behavioral, cognitive, and psychological problems, which can all interact with inhaled treatment. We reviewed the available literature on the clinically relevant side effects of ICSs in the elderly to provide practical measures to properly monitor and manage the risk of ICSs in the geriatric population. Inspection of the mouth, monitoring of ocular pressure, and use of bone-protective drugs may be necessary in patients on prolonged ICS therapy. Above all, the use of the lowest possible ICS dose and a careful re-assessment of the inhalation procedure should be recommended. Taken together, these observations suggest that physicians should use ICSs appropriately for those patients in whom the benefit will outweigh the risk, especially chronic obstructive pulmonary disease (COPD) patients with previous frequent exacerbations. Given the paucity of information on the topic and the need to extrapolate the results from studies with broader age ranges, we strongly encourage the design of specifically tailored clinical studies in the elderly.

Asthma and metabolic syndrome: Current knowledge and future perspectives.

Asthma and obesity are epidemiologically linked; however, similar relationships are also observed with other markers of the metabolic syndrome, such as insulin resistance and dyslipidemia, which cannot be accounted for by increased body mass alone. Obesity appears to be a predisposing factor for the asthma onset, both in adults and in children. In addition, obesity could make asthma more difficult to control and to treat. Although obesity may predispose to increased Th2 inflammation or tendency to atopy, other mechanisms need to be considered, such as those mediated by hyperglycaemia, hyperinsulinemia and dyslipidemia in the context of metabolic syndrome. The mechanisms underlying the association between asthma and metabolic syndrome are yet to be determined. In the past, these two conditions were believed to occur in the same individual without any pathogenetic link. However, the improvement in asthma symptoms following weight reduction indicates a causal relationship. The interplay between these two diseases is probably due to a bidirectional interaction. The purpose of this review is to describe the current knowledge about the possible link between metabolic syndrome and asthma, and explore potential application for future studies and strategic approaches.

Are asthmatics enrolled in randomized trials representative of real-life outpatients?

BACKGROUND/OBJECTIVE: This study was aimed at exploring to what extent populations enrolled in randomized controlled trials (RCTs) of inhalation combination treatment for mild/moderate asthma in adults are fully representative of 'real-life' populations. The following is a retrospective analysis of the clinical records of outpatient subjects with an ascertained diagnosis of asthma. METHODS: A retrospective analysis was performed. Stable conditions, such as smoking habit and chronic diseases other than asthma, were identified as exclusion criteria for RCTs. The selected criteria were then applied to asthmatic outpatients, yielding a population that was potentially eligible for RCTs. RESULTS: Out of 1,909 subjects, 824 (43.2%) met at least one of the exclusion criteria for RCTs. Cigarette smoking (occurring in 34.3% of the entire population), lung diseases other than asthma (5.0%), anxiety and depression (3.3%), arrhythmias (2.3%), and coronary artery disease (1.2%) would have been the most frequent causes for exclusion from RCTs. The proportion of patients excluded from RCTs appears to increase with age, reaching 57.1% in patients aged >85 years. CONCLUSIONS: In a real-life setting, >40% of subjects with mild/moderate asthma are currently treated by protocols based on the results of RCTs for which they would not have been eligible. This proportion increases in elderly patients with comorbidities. These findings limit the generalizability of RCTs and advocate that complementary pragmatic studies be conducted. © 2015 S. Karger AG, Basel.

Safety considerations of inhaled corticosteroids in the elderly.

Inhaled corticosteroids (ICSs) are widely used in the treatment of patients with chronic obstructive pulmonary diseases. However, high-dose regimens and long-term use of ICSs have the potential to cause a variety of local and systemic side effects such as candidiasis, cataracts, glaucoma, and osteoporosis. The use of ICSs can also be associated with the risk of bone fractures, diabetes mellitus and pneumonia. These ICS-related side effects are of particular importance in elderly patients due to the presence of comorbidities and age-related behavioral, cognitive, and psychological problems, which can all interact with inhaled treatment. We reviewed the available literature on the clinically relevant side effects of ICSs in the elderly to provide practical measures to properly monitor and manage the risk of ICSs in the geriatric population. Inspection of the mouth, monitoring of ocular pressure, and use of bone-protective drugs may be necessary in patients on prolonged ICS therapy. Above all, the use of the lowest possible ICS dose and a careful re-assessment of the inhalation procedure should be recommended. Taken together, these observations suggest that physicians should use ICSs appropriately for those patients in whom the benefit will outweigh the risk, especially chronic obstructive pulmonary disease (COPD) patients with previous frequent exacerbations. Given the paucity of information on the topic and the need to extrapolate the results from studies with broader age ranges, we strongly encourage the design of specifically tailored clinical studies in the elderly.

Gemcitabine sensitizes lung cancer cells to Fas/FasL system-mediated killing.

Gemcitabine is a chemotherapy agent commonly used in the treatment of non-small cell lung cancer (NSCLC) that has been demonstrated to induce apoptosis in NSCLC cells by increasing functionally active Fas expression. The aim of this study was to evaluate the Fas/Fas ligand (FasL) system involvement in gemcitabine-induced lung cancer cell killing. NSCLC H292 cells were cultured in the presence or absence of gemcitabine. FasL mRNA and protein were evaluated by real-time PCR, and by Western blot and flow cytometry, respectively. Apoptosis of FasL-expressing cells was evaluated by flow cytometry, and caspase-8 and caspase-3 activation by Western blot and a colorimetric assay. Cytotoxicity of lymphokine-activated killer (LAK) cells and malignant pleural fluid lymphocytes against H292 cells was analysed in the presence or absence of the neutralizing anti-Fas ZB4 antibody, by flow cytometry. Gemcitabine increased FasL mRNA and total protein expression, the percentage of H292 cells bearing membrane-bound FasL (mFasL) and of mFasL-positive apoptotic H292 cells, as well as caspase-8 and caspase-3 cleavage. Moreover, gemcitabine increased CH11-induced caspase-8 and caspase-3 cleavage and proteolytic activity. Cytotoxicity of LAK cells and pleural fluid lymphocytes was increased against gemcitabine-treated H292 cells and was partially inhibited by ZB4 antibody. These results demonstrate that gemcitabine: (i) induces up-regulation of FasL in lung cancer cells triggering cell apoptosis via an autocrine/paracrine loop; (ii) induces a Fas-dependent apoptosis mediated by caspase-8 and caspase-3 activation; (iii) enhances the sensitivity of lung cancer cells to cytotoxic activity of LAK cells and malignant pleural fluid lymphocytes, partially via Fas/FasL pathway. Our data strongly suggest an active involvement of the Fas/FasL system in gemcitabine-induced lung cancer cell killing.

Lung penetration and patient adherence considerations in the management of asthma: role of extra-fine formulations.

The mainstay of management in asthma is inhalation therapy at the target site, with direct delivery of the aerosolized drug into the airways to treat inflammation and relieve obstruction. Abundant evidence is available to support the concept that inflammatory and functional changes at the level of the most peripheral airways strongly contribute to the complexity and heterogeneous manifestations of asthma. It is now largely accepted that there is a wide range of clinical phenotypes of the disease, characterized primarily by small airways involvement. Thus, an appropriate diagnostic algorithm cannot exclude biological and functional assessment of the peripheral airways. Similarly, achievement of optimal control of the disease and appropriate management of specific phenotypes of asthma should be based on drugs (and delivery options) able to distribute uniformly along the bronchial tree and to reach the most peripheral airways. Products developed with the Modulite(®) technology platform have been demonstrated to meet these aims. Recent real-life studies have shown clearly that extra-fine fixed-combination inhaled therapy provides better asthma control than non-extra-fine formulations, thus translating the activity of the drugs into greater effectiveness in clinical practice. We suggest that in patients with incomplete asthma control despite good lung function, involvement of the peripheral airways should always be suspected. When this is the case, treatments targeting both the large and small airways should be used to improve asthma control. Above all, it is emphasized that patient adherence with prescribed medications can contribute to clinical success, and clinicians should always be aware of the role played by patients themselves in determining the success or failure of treatment.

Quality of life analysis of TORCH, a randomized trial testing first-line erlotinib followed by second-line cisplatin/gemcitabine chemotherapy in advanced non-small-cell lung cancer.

INTRODUCTION: The TORCH (Tarceva or Chemotherapy) trial randomized patients with advanced non-small-cell lung cancer to first-line erlotinib followed by second-line cisplatin/gemcitabine versus. standard inverse sequence. The trial, designed to test noninferiority in overall survival, was stopped at interim analysis because of inferior survival in the experimental arm. Quality of life (QoL), a secondary outcome, is reported here. METHODS: QoL was assessed at baseline and every 3 weeks during first-line, using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 and QLQ-lung cancer specific module (LC13). Mean changes from baseline within arms were reported. QoL response and time-to-deterioration of QoL using a competing-risk approach were compared between treatment arms. RESULTS: Six hundred and thirty patients (83%) completed baseline questionnaires. Compliance was affected by differential treatment efficacy, but was similar between arms for patients without progression or death. Significant differences in QoL responses were observed favoring chemotherapy for pain, sleeping, dyspnea, diarrhea, and favoring erlotinib for vomiting, constipation, sore mouth, and alopecia. In the small subset of patients with EGFR-mutated tumors, all selected items (global QoL, physical functioning, cough, dyspnea and pain) improved, whereas worsening or no change was observed in wild-type patients. Improvement was particularly evident in the first-line erlotinib arm as for global QoL and physical functioning. CONCLUSIONS: QoL was impacted by differential toxicity and efficacy between arms. Functional domains and global QoL did not differ, although some symptoms were better controlled with chemotherapy in unselected non-small-cell lung cancer patients.

Altered CD94/NKG2A and perforin expression reduce the cytotoxic activity in malignant pleural effusions.

CD94/NKG2A is an inhibitory receptor expressed by NK cells and cytotoxic lymphocytes and, upon activation by HLA-E, downregulates the cytolytic activities of these cells thus representing a tumour immune escape mechanism. This study was aimed at assessing whether cytotoxic lymphocytes (CD8+) and NK cells from malignant pleural effusions have a deregulated expression of CD94/NKG2A. The expression of membrane CD94/NKG2A and perforin was evaluated by flow-cytometry in CD8+ and NK cells from pleural effusions and autologous peripheral blood of cancer (n=19) and congestive heart failure (CHF) (n=11) patients. Intracellular CD94/NKG2A expression was evaluated by flow-cytometry in pleural effusion CD8+ and NK cells from cancer patients (n=10). Cytotoxic activity against cancer cells exerted by pleural and autologous peripheral blood T lymphocytes from cancer patients was assessed by flow-cytometry assay. Pleural CD8+ from cancer patients showed a reduced expression of membrane CD94/NKG2A and perforin when compared to autologous peripheral blood and CHF pleural effusions. Reduced numbers of NK cells were present in pleural effusions from both cancer and CHF patients. Pleural NK from cancer patients showed a reduced expression of membrane CD94/NKG2A and perforin when compared to autologous peripheral blood. Pleural T lymphocytes from cancer patients exhibited a reduced cytotoxic activity against cancer cells when compared to autologous peripheral blood T lymphocytes. The intracellular expression of CD94/NKG2A in CD8+ and NK cells from cancer patients was higher than membrane expression. In conclusion, this study provides compelling evidences of new mechanisms underlying the reduced host defence against cancer within the pleural space.

A 15-year-old boy with anterior chest pain, progressive dyspnea, and subcutaneous emphysema of the neck.

We describe the case of an adolescent who was admitted to the hospital because of sudden occurrence of chest pain, dyspnea and subcutaneous emphysema. On admission, physical examination revealed subcutaneous crepitations in the superior part of the rib cage, and auscultation of the chest showed widespread wheezing. The radiological assessment confirmed the diagnosis of pneumomediastinum and pneumothorax. A follow-up CT scan performed one week after the admission showed almost complete resolution of the radiological alterations. At the following visits, the patient was asymptomatic, but reported to have suffered from frequent episodes of rhinorrea, sneezing, nasal blockage, and sometimes, chest tightness, especially during exposure to pets and/or windy weather. Skin prick testing showed sensitivities to dermatophagoides pteronyssinus and farinae, grass pollen and dog dander. Spirometry documented significant improvement in lung function after short-acting bronchodilator, allowing for the diagnosis of asthma to be made. Although pneumomediastinum may be a complication of various respiratory diseases, including asthma, it has never been reported as the first presentation of underlying bronchial asthma. Herein, the physiopathological mechanisms, the diagnostic procedures and treatment of pneumomediastinum in asthma are discussed. We suggest that the diagnosis of asthma should be considered in the differential diagnosis of pneumomediastinum in adolescence.

Pretreatment quality of life and functional status assessment significantly predict survival of elderly patients with advanced non-small-cell lung cancer receiving chemotherapy: a prognostic analysis of the multicenter Italian lung cancer in the elderly study.

PURPOSE: To study the prognostic value for overall survival of baseline assessment of functional status, comorbidity, and quality of life (QoL) in elderly patients with advanced non-small-cell lung cancer treated with chemotherapy. PATIENTS AND METHODS: Data from 566 patients enrolled onto the phase III randomized Multicenter Italian Lung Cancer in the Elderly Study (MILES) study were analyzed. Functional status was measured as activities of daily living (ADL) and instrumental ADL (IADL). The presence of comorbidity was assessed with a checklist of 33 items; items 29 and 30 of the European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30 (EORTC QLQ-C30) were used to estimate QoL. ADL was dichotomized as none versus one or more dependency. For IADL and QoL, three categories were defined using first and third quartiles as cut points. Comorbidity was summarized using the Charlson scale. Analysis was performed by Cox model, and stratified by treatment arm. RESULTS: Better values of baseline QoL (P = .0003) and IADL (P = .04) were significantly associated with better prognosis, whereas ADL (P = .44) and Charlson score (P = .66) had no prognostic value. Performance status 2 (P = .006) and a higher number of metastatic sites (P = .02) also predicted shorter overall survival. CONCLUSIONS: Pretreatment global QoL and IADL scores, but not ADL and comorbidity, have significant prognostic value for survival of elderly patients with advanced non-small-cell lung cancer who were treated with chemotherapy. Using these scores in clinical practice might improve prognostic prediction for treatment planning.

Light smoking and dependence symptoms in high-school students.

In high-school students, prevalence of smoking is high but few studies analyzed smoking in the student population according to nicotine content of smoked cigarettes and gender. We analyzed the responses to a questionnaire, including the modified Fagerström Tolerance Questionnaire (FTQ), administered to 555 students (382 males, 173 females) of a professional high school in Palermo, Italy, to assess the prevalence in both genders of: (1) smoking "light" and high nicotine (HN) cigarettes; (2) signs of nicotine dependence and (3) respiratory symptoms. Nicotine content of habitually smoked cigarettes was considered as "light" if 0.8 mg; as high if >0.8 mg. Forty-four percent of students smoked, without differences between genders. Two-thirds of the total sample reported "light" cigarette smoking (76.7% of females vs. 62.0% of males, P<0.05). On average, "light" cigarette smoking was associated with lower pack/year and FTQ global score compared to HN smoking. However, when FTQ global score was analyzed by taking into account pack/year, no major difference was found between "light" and HN cigarette smokers. Cough with phlegm and breathlessness were more frequently reported by smoking than non-smoking students, without differences between "light" and HN cigarette smokers. About 50% of smoking students reported having tried to quit, while only 3.4% of students were ex-smokers. "Light" smoking was common in high school students, especially among females. Dependence appeared more influenced by the smoking history than by nicotine content. Respiratory symptoms were similar in "light" and HN cigarette smokers.

Sleep disorders in the elderly with and without chronic airflow obstruction: the SARA study.

OBJECTIVE: Our objectives were to test the hypothesis that, in the geriatric population, chronic airway obstruction is associated with a higher prevalence of sleep disturbances; to identify the main correlates of sleep disturbances, and to verify whether asthma and COPD patients have different patterns of sleep disturbances. METHODS: The EPESE questionnaire was administered to 734 patients aged 65 years and over with asthma or chronic obstructive pulmonary disease (cases) and 1237 individuals of comparable age who were free of respiratory disease but not of other chronic conditions (controls). Four sleep disturbances were quantified: difficulty in falling asleep, nocturnal awakening, morning tiredness, and early awakening. Multidimensional assessment of demographic data, personal history, clinical, and functional status was performed. Independent correlates of sleep disturbances were identified by logistic regression analysis. RESULTS: One or more sleep disturbances were reported by 445 cases and 697 controls (60.6% vs. 56.4%, ns). Morning tiredness and early awakenings were more prevalent among cases (38% vs. 27.8%, p < 0.001, and 35.1% vs. 28%, p < 0.001, respectively). Depression, as assessed by the 15-item Geriatric Depression Scale, was the most significant independent correlate for all sleep scores. Both being a case and having arthritis were independent correlates of three out of the four sleep disturbances. CONCLUSIONS: Selected sleep disturbances are more common among elderly patients with chronic airway diseases than in those with chronic non-respiratory diseases. Depressed mood and coexisting arthritis are the most relevant independent correlates of sleep disturbances.

Biologically active intercellular adhesion molecule-1 is shed as dimers by a regulated mechanism in the inflamed pleural space.

Intercellular adhesion molecule-1 (ICAM-1) is an adhesion molecule that plays a crucial role in cell-cell interactions involved in the recruitment of cells and immune responses. Under some circumstances, ICAM-1 is found as a soluble protein that has the potential to influence the nature of immunoinflammatory responses. By examining cells and fluid from the pleural compartment of patients with cancer, tuberculosis, and congestive heart failure, the cellular source, conformation, control, and biological activity of soluble ICAM-1 (sICAM-1) were investigated. The results suggest that dimeric sICAM-1 was released locally in the pleural compartment of tuberculous and malignant effusions. sICAM-1 was shed from preexpressed surface ICAM-1 rather than produced de novo, and both CD45-positive leukocytes and cytokeratin-positive epithelial and mesothelial cells expressed ICAM-1, suggesting multiple cellular sources for sICAM-1. The expression of sICAM-1 was regulated because pleural macrophages caused release of sICAM-1 via a tumor necrosis factor-alpha-dependent mechanism. The functional significance of sICAM-1 was demonstrated by showing that pleural sICAM-1 interfered with conjugate formation between LAK cells and K562 cells, suggesting that pleural sICAM-1 plays an immunosuppressive role by inhibiting adhesion of cytotoxic lymphocytes and tumor cells. Thus, sICAM-1 is shed from the surface of cells in a regulated manner and has the potential to influence the immune response in the pleural space.