Respiratory syncytical virus-induced chemokine expression in the lower airways: eosinophil recruitment and degranulation.

Characterization of chemokine expression patterns in virus-infected epithelial cells provides important clues to the pathophysiology of such infections. The aim of this study was to determine the chemokine response pattern of respiratory epithelium when infected with respiratory syncytial virus (RSV). Macrophage inflammatory protein-1-alpha (MIP-1-alpha), interleukin-8 (IL-8), and RANTES concentrations were measured from RSV-infected HEp-2, MRC-5, and WI-38 cell culture supernatants daily following infection. Additionally, MIP-1-alpha, IL-8, and RANTES concentrations were measured from lower respiratory secretions obtained from 10 intubated infants (0-24 mo) with RSV bronchiolitis, and from 10 control subjects. Our results indicate that respiratory epithelial cells respond to RSV infection by producing MIP-1-alpha, IL-8, and RANTES. Production of MIP-1-alpha required ongoing viral replication, whereas RANTES and IL-8 could be elicited by inactivated forms of the virus. MIP-1-alpha, RANTES, and IL-8 were also present in lower airway secretions obtained from patients with RSV bronchiolitis. Eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN), the eosinophil secretory ribonucleases, were detected in lower airway secretions from RSV-infected patients; ECP concentrations correlated with MIP-1-alpha concentrations (r = 0.93). We conclude that MIP-1-alpha is present in the lower airways during severe RSV disease. The correlation between MIP-1-alpha and ECP concentrations suggests a role for eosinophil degranulation products in the pathogenesis of RSV bronchiolitis.     

IL-8 and neutrophil elastase levels in the respiratory tract of infants with RSV bronchiolitis.

The aim of this study was to determine whether interleukin (IL)-8 is released within the upper respiratory tract of infants during respiratory syncytial virus (RSV) bronchiolitis and whether the large number of polymorphonuclear neutrophils (PMNs) present in the respiratory tract of these infants are contributing to the inflammation through release of inflammatory mediators. Twenty-seven infants with acute bronchiolitis were recruited during one winter epidemic and 20 infant control subjects were recruited from a cohort participating in a community-based vaccine study. Samples of airways fluid were obtained using nasal lavage. The lavage fluid was spun to remove the cells, and the supernatant was stored at -70 degrees C. The supernatants were subsequently assayed for the presence of IL-8, total human neutrophil elastase (HNE) and neutrophil elastase activity. In the children with bronchiolitis compared with control infants, elevated levels of IL-8 (median (range) 1.53 (0-153) versus 0 (0-5.6) ng x mL(-1)) HNE (136 (32-694) versus 14 (0-516) ng x mL(-1)) and elastase activity (4 (1-220) versus 1 (0-339) mU x mL(-1)) were found. These results indicate that interleukin-8 is released in the upper respiratory tract in response to respiratory syncytial virus infection and suggest that polymorphonuclear neutrophil products are playing an important role in the inflammatory response to respiratory syncytial virus infection in infants with acute bronchiolitis. This contrasts with the predominantly eosinophilic response evident in atopic upper and lower respiratory tract disease.     

DNase treatment for atelectasis in infants with severe respiratory syncytial virus bronchiolitis.

Respiratory insufficiency due to respiratory syncytial virus (RSV) bronchiolitis is partly due to the abundance of thickened mucus and the inability to clear it from the airways. Mucus in RSV bronchiolitis contains necrotic inflammatory and epithelial cells. The viscoelastic properties of purulent airway secretions are largely due to the presence of highly polymerized deoxyribonucleic acid (DNA). Recombinant human deoxyribonuclease (rhDNase) is known to liquefy such mucus in patients with cystic fibrosis, whereas case reports described a beneficial effect in other respiratory disorders. The authors hypothesized that rhDNase would diminish atelectasis and mucus plugging in infants with severe RSV bronchiolitis. Two infants with RSV bronchiolitis with massive unilateral atelectasis in whom mechanical ventilation was imminent due to exhaustion, and three mechanically ventilated infants (two neonates, one with bronchopulmonary dysplasia) with RSV bronchiolitis with pneumonia received treatment with 2.5 mg nebulized rhDNase twice daily. Following administration of nebulized recombinant human deoxyribonuclease, clinical and radiological parameters improved quickly. Mechanical ventilation could be avoided in two infants while in three infants on artificial ventilation, clinical recovery started following the first dose of the drug. A therapeutic trial of recombinant human deoxyribonuclease may be an option in the treatment for atelectasis in severe or complicated respiratory syncytial virus bronchiolitis in infancy.     

The interaction of neutrophils with respiratory epithelial cells in viral infection

Viral respiratory infection is very common. Respiratory syncytial virus (RSV) infects almost all children during the first 2 years of life. Respiratory syncytial virus is the most frequent cause of bronchiolitis, which is strongly linked with asthma. However, the pathophysiology of RSV bronchiolitis is unclear. Neutrophils are the predominant airway leucocytes in RSV bronchiolitis and other viral infections. Neutrophils and their products are likely to play an important role in viral infection. Current evidence indicates that: (i) viral infection of epithelial cells increases the production of neutrophil chemoattractants or chemokines, which induce neutrophil migration into the inflammatory sites; (ii) the expression of adhesion molecules on neutrophils and epithelial cells is up-regulated in viral infection, and neutrophil-epithelial adhesion is increased; (iii) neutrophils augment epithelial damage and detachment induced by viral infection and contribute to the pathophysiology of viral disease; (iv) neutrophil apoptosis is up-regulated in RSV infection, which may be an in vivo mechanism to limit neutrophil-induced epithelial damage; (v) inhibitors of chemokines, adhesion molecules or neutrophil proteases may be useful in prevention of neutrophil-induced epithelial damage. In conclusion, neutrophils play an important role in viral infection, and intervention to prevent neutrophil-induced epithelial damage may be a potential clinical therapy.     

Relationship between respiratory syncytial virus bronchiolitis and future obstructive airway diseases.

Evidence from a large number of prospective case-control studies shows that respiratory syncytial virus (RSV) bronchiolitis in infancy is often associated with recurrent wheezing and asthma during subsequent years. However, wheezing tends to diminish and most studies show no significant increase in wheezing compared to controls by school age or adolescence. An unresolved question is whether severe RSV infection during infancy causes the respiratory sequelae or inherent abnormalities predispose an infant to develop severe respiratory infection and sequelae, i.e. RSV is associated with the development of pulmonary sequelae. Studies on long-term outcome of RSV bronchiolitis are reviewed from an evidence-based perspective. The majority of prospective placebo-controlled studies do not show any long-term beneficial effects of corticosteroid treatment, i.e. the risk of subsequent wheezing is not diminished by the treatment. The evidence for an increased risk of allergic sensitization after RSV bronchiolitis is not nearly as strong as the evidence for an increased risk of subsequent wheezing. In fact, most studies do not show any significant increase in atopy after RSV bronchiolitis. This suggests that the increased risk of wheezing after RSV is not linked to an increased risk of atopy. There are some indications that infants who develop severe RSV and subsequent wheezing may have aberrations that predate the RSV infection. To decide whether respiratory syncytial virus bronchiolitis causes, or is associated with the respiratory sequelae (or with subsequent allergy), it will be necessary to conduct prospective, randomized studies, where the cytokine profile prior to bronchiolitis onset is known. Such studies should preferably include some form of intervention against respiratory syncytial virus. A more complete understanding of the risk factors for severe respiratory syncytial virus infection and the role of respiratory syncytial virus infection in the initiation of asthma is needed as a basis for large-scale and cost-effective programmes to prevent respiratory syncytial virus-related morbidity.     

儿童百日咳与支气管哮喘关系的研究进展

支气管哮喘(哮喘)是一种多因素异质性疾病,严重影响儿童的身心健康。对于其发病原因及机制的研究一直是学者们关注的重点。近年来,呼吸道合胞病毒、鼻病毒、肺炎支原体等病原体感染与哮喘的关系逐渐明确,但是百日咳与哮喘之间的关系尚不明确。有研究认为百日咳杆菌感染后可诱导IgE的产生、激活Th2细胞并诱导Th17免疫应答,加强中性...     

Eosinophil cationic protein in infants with respiratory syncytial virus bronchiolitis: predictive value for subsequent development of persistent wheezing

Infants with acute bronchiolitis during the first months of life are at increased risk of developing persistent wheezing and bronchial asthma later in life. The study of eosinophil cationic protein (ECP) suggests that eosinophil-related inflammatory mechanisms may play a role in respiratory syncytial virus (RSV) bronchiolitis. The aim of our study was to verify whether serum ECP (s-ECP) measurements are useful in predicting the development of persistent wheezing in children affected by RSV bronchiolitis during a 5 years follow-up period. Forty-eight infants were enrolled prospectively (mean age: 153.5 days). All had a clinical and radiological diagnosis of acute bronchiolitis and confirmed RSV infection. Peripheral eosinophil counts, levels of s-ECP, and serum IgE concentrations were measured during bronchiolitis. Five years later the children were re-evaluated in regard to their respiratory symptoms (standardized questionnaires) and atopic status (specific IgE levels). We observed significantly higher s-ECP levels (P < 0.001) at enrollment in subjects who developed persistent wheezing compared to subjects who did not show late wheezing. Initial s-ECP values allowed significant and correct prediction of persistent wheezing (P < 0.001). The risk to develop respiratory symptoms was 9.73 higher for infants with s-ECP levels > or = 8 microg/L than for those with s-ECP levels <8 microg/L (P < 0.0001). In conclusion, our study suggests that s-ECP levels in infants with bronchiolitis are useful in predicting the risk to develop wheezing in the subsequent 5 years.     

Respiratory syncytial virus--viral biology and the host response

Respiratory syncytial virus (RSV) is the most important cause of respiratory tract infection in infants. We have an incomplete understanding of the reasons why some infants are more severely affected by RSV than others. There is no effective antiviral treatment for the infection. Advances in our understanding of the biology of RSV, particularly in relation to the attachment protein G and the fusion protein F, have revealed potential targets for new antiviral therapies and vaccine development. In response to RSV infection an intense inflammatory response is triggered, mediated initially by the infected airway epithelial cells. Cell mediated responses are important in controlling the extent of infection and in viral clearance. Humoral responses are important in protection. There is early evidence that genetic variation of the host response can influence the outcome of RSV-induced bronchiolitis.     

Increased Eosinophilic Cationic Protein in Nasal Fluid in Hospitalized Wheezy Infants with RSV Infection

BackgroundRespiratory syncytial virus (RSV) is a major respiratory pathogen which causes bronchiolitis with dyspnea and wheezing in children less than 2 years old. RSV bronchiolitis in infancy severe enough to cause hospitalization might be a risk factor for allergic sensitization and bronchial asthma in future. However, the pathophysiology behind this development has not been clearly characterized. To evaluate the existence of airway inflammation and characteristic of RSV bronchiolitis, we analyzed and compared the concentrations of eosinophilic cationic protein (ECP) in nasal fluid and plasma.MethodsFrom 69 infants (aged < 2 years) hospitalized for possible lower respiratory tract infections including RSV infection, we collected nasal fluid and plasma and determined the ECP concentrations.ResultsECP concentrations in nasal fluid were significantly higher in patients with wheezing and/or bronchial rales than in patients without them (1733 ± 660 ng/mL vs 680 ± 450 ng/mL, p = 0.018), and those of the respiratory syncitial virus-infected group were significantly higher than those of the uninfected group (p = 0.04). Meanwhile, there was no significant difference in plasma ECP levels between patients with wheezing and patients without wheezing, and no significant difference between RSV-infected and other pathogen-infected patients. There were significant correlations between nasal fluid ECP concentrations and both neutrophil and eosinophil counts in the peripheral blood.ConclusionsNasal fluid ECP concentrations are increased in infants with lower respiratory infections including RSV infection accompanied with wheezing. ECP probably originates from neutrophils as well as eosinophils migrated into airways. The monitoring of ECP concentration in nasal fluid may be useful for evaluating leukocyte (including eosinophils and neutrophils)-mediated airway inflammation during infancy and its severity.     

Bronchiolitis

Bronchiolitis is a distressing, potentially life-threatening respiratory condition that affects young babies. Around 2-3% of all infants younger than 1 year are admitted to hospital with bronchiolitis, usually during the seasonal epidemic. The majority of these infants are infected with respiratory syncytial virus and all have an intense inflammatory response in their airways. Although most infants recover, they have an increased risk of recurrent wheezing. Although bronchiolitis is common, little is known about what causes infants to be susceptible. Diagnostic interventions have little effect on clinical outcome, and apart from supportive measures, there is no specific treatment. Bronchiolitis therefore presents an intriguing clinical conundrum and a major challenge to researchers. High quality clinical studies are needed to clarify assessment of disease severity and criteria for hospital admission, particularly the use of pulse oximetry and chest radiography. Careful mapping of the inflammatory pathways in the pathogenesis of bronchiolitis should lead to development of new therapies to alleviate symptoms.     

Does blood eosinophilia in wheezing infants predict later asthma? A prospective 18-20-year follow-up.

Although eosinophilia in wheezing infants predicts subsequent wheezing, it is not known how long the association persists. Our aim was to evaluate the connection between blood eosinophilia in infancy and later wheezing/asthma until adulthood, with special attention paid to infection-induced changes in blood eosinophils. We have prospectively followed up 83 infants until adulthood after hospitalization for bronchiolitis in 1981-1982. Blood eosinophils were determined in a counting chamber on admission and on convalescence 4-6 weeks later. Data on recurrent wheezing and asthma were registered prospectively at five follow-ups until the age of 18-20 years. The median (25th-75th percentile) eosinophil count was 0.100 x 10E9/L (0.028-0.321) on admission and 0.231 x 10E9/L (0.119-0.368) on convalescence. Eosinophils during bronchiolitis or infection-induced changes in eosinophils were not associated with subsequent wheezing/asthma at any age during the follow-up. The result was similar in univariate and multivariate analyses. Respiratory syncytial virus (RSV) bronchiolitis patients had lower eosinophils on admission than non-RSV cases, but the changes induced by RSV or other infection did not differ significantly. In univariate analyses, elevated eosinophils on convalescence predicted later wheezing until 3-4 years of age. In multivariate analysis, adjusted for RSV etiology, age on admission, and histories of earlier wheezing and atopy, elevated eosinophils on convalescence predicted increased asthma risk at 2-3 years (OR, 2.26; 95% CI, 1.29-3.95), at 3-4 years (OR, 2.24; 95% CI, 1.27-3.95), and at 8.5-10 years (OR, 2.16; 95% CI, 1.01-4.64). Eosinophilia outside, but not during, infection predicted recurrent wheezing until preschool and early school years but not thereafter.     

Bronchiolitis to asthma: a review and call for studies of gene-virus interactions in asthma causation

Viral infections are important causes of asthma exacerbations in children, and lower respiratory tract infections (LRTIs), caused by viruses such as respiratory syncytial virus (RSV) and rhinovirus (RV), are a leading cause of bronchiolitis in infants. Infants hospitalized with bronchiolitis are at significantly increased risk for both recurrent wheezing and childhood asthma. To date, studies addressing the incidence of asthma after bronchiolitis severe enough to warrant hospitalization have focused almost exclusively on RSV, but a number of recent studies suggest that other respiratory pathogens, including RV, may contribute as well. It is not known whether viral bronchiolitis directly contributes to asthma causation or simply identifies infants at risk for subsequent wheezing, as from an atopic predisposition or preexisting abnormal lung function. Alternatively, the properties of the infecting virus may be important. Thus, many possible determinants exist that may contribute to the severity of bronchiolitis and the subsequent development of asthma. One such determinant is the potential involvement of genetic susceptibility loci to asthma after viral bronchiolitis, a critical area that is just beginning to be evaluated. By clarifying the roles of both host- (genetic) and virus- (environment) specific factors that contribute to the frequency and severity of viral LRTI, it may be possible to determine if severe LRTIs cause asthma, or if asthma susceptibility predisposes patients to severe LRTI in response to viral infection. Characterizing these relationships offers the potential of identifying at-risk hosts in whom preventing or delaying infection could alter the phenotypic expression of asthma.     

Type 1 and type 2 cytokine imbalance in acute respiratory syncytial virus bronchiolitis

We examined the in vivo immune response of infants to natural respiratory syncytial virus (RSV) infection through analysis of cytokine levels in nasal lavage fluid and stimulated peripheral blood mononuclear cells. Eighty-eight babies with at least one parent with atopy and asthma were prospectively studied through their first winter. Twenty-eight infants had an upper respiratory tract infection where RSV was detected, of whom nine developed signs of acute bronchiolitis. Nasal lavage specimens were assayed for interferon-gamma, interleukin (IL)-4, IL-10, and IL-12 and the RSV load determined by quantitative polymerase chain reaction. Messenger RNA (mRNA) was extracted from stimulated peripheral blood mononuclear cells and interferon-gamma, IL-4, IL-12, and IL-18 mRNA levels determined by polymerase chain reaction. Cytokine profiles were analyzed in relation to clinical outcome. The IL-4/interferon-gamma ratio for infants with acute bronchiolitis was elevated in nasal lavage fluid on both Days 1-2 (p = 0.014) and Days 5-7 (p = 0.001) of the illness compared with infants with upper respiratory tract infection alone. Those with acute bronchiolitis demonstrated a higher IL-10/IL-12 ratio (p = 0.0015) on Days 1-2. IL-18 mRNA levels were reduced (p = 0.019) and the IL-4/interferon-gamma ratio elevated (p = 0.01) in stimulated peripheral blood mononuclear cells from infants with acute bronchiolitis. There was no difference in initial RSV load. These data strongly implicate excess type 2 and/or deficient type 1 immune responses in the pathogenesis of RSV bronchiolitis.     

Acute and long-term effects of infection by the respiratory syncytial virus in children with congenital cardiac malformations

All newborn infants have limited pulmonary reserve compared with older children. This puts them at increased risk of respiratory complications, such as those associated with infection by the respiratory syncytial virus. Young children with congenital cardiac disease are particularly likely to suffer severe disease related to infection by the virus. In these children, the extreme vulnerability of the lung to pulmonary oedema is compounded by the additional burden caused by the respiratory syncytial virus. In addition to the well-documented acute pulmonary effects of infection with the respiratory syncytial virus, there may also be consequent long-term respiratory morbidity. Clinical studies have shown that infection by the virus in infancy is associated with a higher risk of developing subsequent bronchial obstructive disease. Much debate surrounds the mechanisms underlying this association. It is thought that a combined immunological and neurogenic response mechanism is likely. Prevention of severe respiratory disease in infants and young children with congenital heart disease due to infection by the virus may, therefore, offer both immediate and long-term benefits. Indeed, an increasing body of evidence supports this hypothesis, indicating a clinical rationale for prophylaxis against the virus in infancy, in order to reduce the chance of developing reactive airways disease and asthma in later life.     

Effects of respiratory syncytial virus persistence on airway responsiveness and inflammation in guinea-pigs.

Recurrent wheezing and asthma often develop after acute respiratory syncytial virus (RSV) bronchiolitis, but the mechanisms of these sequelae are poorly understood. Using a guinea-pig model of human RSV lung infection, the effects of long-term viral persistence on three hallmarks of asthma: nonspecific airway responsiveness, airway inflammation and airway remodelling were examined. Guinea-pigs were studied 100 days after intranasal instillation of either human RSV or uninfected vehicle, using: 1) acetylcholine challenge to test for airway hyperresponsiveness (AHR); 2) lung histology to quantify the numbers of airway eosinophils and metachromatic cells (mast cells/basophils); 3) airway morphometry of the areas of the airway subepithelial connective tissue, smooth muscle and adventitia, to test for airway remodelling; and 4) immunohistochemistry to identify lung cells containing RSV antigens. The RSV-inoculated group had significantly elevated AHR and airway eosinophils compared to uninfected control animals (p<0.05). There were no significant differences between the two groups in terms of numbers of airway metachromatic cells, or the areas of subepithelial connective tissue, smooth muscle or adventitia. Viral proteins were identified by immunohistochemistry within several types of lung cells. In conclusion, long-term persistence of respiratory syncytial virus in the guinea-pig lung is associated with airway hyperresponsiveness and airway eosinophilia, and these changes may be pertinent to the pathogenesis of postbronchiolitis wheezing and asthma in children.     

Respiratory syncytial virus bronchiolitis: disease severity, interleukin-8, and virus genotype

In infants with respiratory syncytial virus (RSV) bronchiolitis, we investigated whether disease severity is associated with the genotype of the infecting virus, or with the infant's immunological response to the infection, as determined by measurement of interleukin-8 mRNA in the nasopharyngeal aspirate. This was a cross-sectional observational study, performed in the Accident and Emergency Department, wards, and Intensive Care Unit of a large pediatric hospital. Participants included 276 infants with respiratory syncytial virus infection. Outcome variables included: disease severity (infants requiring oxygen or ventilation were classified as having severe disease); RSV virus genotype (determined according to typing scheme based on the nucleoprotein and G glycoprotein genes); and amount of interleukin-8 mRNA in the nasopharyngeal aspirate, as measured by a semiquantitative polymerase chain reaction assay. This was corrected for the amount of cellular material in the sample by expressing it relative to mRNA for a constitutively expressed gene, HGPRT. We found a highly significant association between the ratio of interleukin-8 mRNA/HGPRT mRNA in the nasopharyngeal aspirate and the occurrence of severe disease. Odds ratio per unit increase of interleukin-8 mRNA/HGPRT mRNA was 1.15 (95% CI, 1.06, 1.24), P = 0.0004. There was no association between virus genotype and either disease severity or amount of interleukin-8 mRNA/HGPRT mRNA. In conclusion, there is a strong, dose-related association between interleukin-8 mRNA produced locally in the airways and disease severity, and a lack of association with virus genotype. This suggests that clinical manifestations of respiratory syncytial virus bronchiolitis are determined by local immunological responses to infection, rather than by characteristics of the infecting virus.     

Acute and long-term effects of viral bronchiolitis in infancy

About 1% of infants are admitted to hospital with acture bronchiolitis; 85% of cases are caused by infection with Respiratory Syncytial Virus (RSV). The pathophysiological changes during the acute illness are inflammatory obstruction in the small airways with submucosal cellular infiltration, epithelial necrosis and mucous plugging; FRC increases and dynamic compliance falls. Failure to respond to bronchodilator drugs suggests that muscle spasm contributes relatively little to the airway narrowing. Affected infants become increasingly dyspnoeic and hypoxic for 3–4 days then spontaneously improve. After an attack of acute bronchiolitis up to 75% of children have recurrent lower respiratory tract symptoms, many continue to have hyperinflated lungs and bronchial hyperresponsiveness. In the majority, symptoms of cough and wheezing have subsided by the time they start school, but abnormalities of small airway function are detectable at least 13 years later. Children with a genetic predisposition to atopy do not appear to have an increased risk of developing bronchiolitis. Evidence of genetic predisposition to bronchial hyperresponsiveness in those with persistent wheezing is controversial. There is little to suggest that neonatal lung damage or an adverse home environment are important factors in determining susceptibility to post-bronchiolitis wheezing. IgE antibodies to RSV, and leucotriene C4, are found more frequently in the respiratory secretions of infants who wheeze during and after bronchiolitis than in those who do not. The possibility of viral-induced alteration of the immune response at the time of infection needs further investigation.     

嗜酸粒细胞在气道激活机制中的研究进展

支气管哮喘是一种以嗜酸粒细胞(eosinophils,EOS)和肥大细胞浸润、气道高反应性为主要病理生理特征的慢性气道炎症,其中EOS在气道的激活对疾病的发生发展起着关键作用.气道中的EOS主要来源于外周血,极小部分来源于气道内的嗜酸粒细胞前体祖细胞,前者早在外周血中便在内皮细胞的作用下开始启动激活,之后气道上皮细胞通...     

Eosinophils and major basic protein damage but do not detach human amniotic epithelial cells.

Damage and detachment of epithelial cells is thought to contribute to the pathologenesis of asthma. Both eosinophils and neutrophils are found in asthmatic airways and several studies have suggested that eosinophils may be responsible for the epithelial cell detachment of asthma. To compare the capacity of purified human eosinophils and neutrophils to mediate epithelial cell detachment, we utilized a human amniotic epithelial cell-basement membrane model that we have recently described. Activated eosinophils induced little detachment at 4 h (less than 10% detachment), which contrasted with that seen with equivalent numbers of identically handled neutrophils (29 +/- 6% detachment, p less than .05). In contrast, eosinophils did induce damage to epithelial cells to an extent similar to neutrophils when assessed using a 51Cr release assay (17 +/- 6% and 18 +/- 9% release of 51Cr, respectively). When purified preparations of the major eosinophil-derived protein major basic protein (MBP) were studied, similar effects on epithelial cells were observed, i.e., damage (77 +/- 13% release of 51Cr) without detachment (less than 5% cell detachment). These data suggest that neutrophils are more effective in inducing detachment of human epithelial cells, whereas both eosinophils and neutrophils damage human epithelial cells.