Are paediatricians failing at school?
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Child↗
Biomedical subjects
K D Forsyth
Publications and source records attributed to K D Forsyth.
Leucocyte populations in respiratory syncytial virus-induced bronchiolitis.
OBJECTIVES: To enumerate the cellular composition of the airways in infants with acute bronchiolitis. METHODOLOGY: Cells were obtained by airway lavage from the upper and lower airway and the peripheral blood of infants with respiratory syncytial virus (RSV)+ bronchiolitis, RSV- bronchiolitis and age-matched controls. RESULTS: Neutrophils are the predominant cells present in the upper and lower airway. Neutrophils are present at a higher number/unit volume in the airway than in the peripheral blood. CONCLUSIONS: Neutrophils, being the dominant cellular infiltrate into the airway, are likely to contribute to the pathophysiology of bronchiolitis. Therapies targeted at limiting neutrophil influx or neutrophil-mediated damage in the airway may have a therapeutic role.
Bronchiolitis, Viral↗
Adhesion molecule expression on epithelial cells infected with respiratory syncytial virus.
Respiratory epithelium is both a target and an effector of airway inflammation. Adhesion molecules on epithelium play an important role in a variety of airway diseases. Respiratory syncytial virus (RSV) is the most important pathogen for airway diseases in infants. The expression of adhesion molecules on epithelium in RSV infection, however, is unclear. The expression of selected adhesion molecules and major histocompatibility complex (MHC) class I and II antigens on a human alveolar type II epithelial cell line (A549) infected with RSV was investigated by means of flow cytometry and immunocytochemistry. The results showed that intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were expressed on A549 cells at a low level. E-cadherin and MHC class I antigen were constitutively expressed on the cells. RSV infection of A549 cells significantly upregulated the expression of ICAM-1, VCAM-1 and MHC class I and II antigens on these cells. RSV infection also altered the expression of E-cadherin on A549 cells. Immunostaining showed that E-cadherin was mainly upregulated around or in RSV-induced giant cells. These data suggest that respiratory syncytial virus infection of respiratory epithelial cells enhances the expression of adhesion molecules and major histocompatibility complex antigens. These changes may play an important role in the pathophysiology of respiratory syncytial virus disease.
Cell Adhesion Molecules↗
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.
Animals↗
Immune and inflammatory responses in sudden infant death syndrome.
Infancy is a time of unparalleled infection exposure. Coming from the privilege of the uterus, the newborn infant must make appropriate immune responses following infection that eliminates the infection but protects the host. There is evidence that in sudden infant death syndrome (SIDS) subjects there is a background of recent 'trivial' infection and immunological/inflammatory reactivity. This immunological/inflammatory reactivity is seen in enhanced pulmonary immunoglobulins and T-cell activation. It may be that in certain SIDS cases a trivial infection triggers an exaggerated inflammatory response, inducing cytokine cascades and eventual demise of the infant.
Anaphylaxis↗
Plasma surfactant protein-B is elevated in infants with respiratory syncytial virus-induced bronchiolitis.
Respiratory syncytial virus (RSV) is the most frequent cause of bronchiolitis. However the pathophysiology of bronchiolitis is unclear. Leukocytes, especially neutrophils, may play an important role in the pathogenesis of bronchiolitis. Whereas we have previously shown that neutrophils augment epithelial leakage and detachment in RSV infection in vitro, it is unknown whether epithelial damage occurs in vivo in infants with RSV bronchiolitis. We hypothesized that respiratory epithelial damage occurs in infants with RSV bronchiolitis and that surfactant proteins leak into the circulation. The plasma concentrations of surfactant protein-A and surfactant protein-B in infants with RSV bronchiolitis were measured by ELISA. Plasma immunoreactive surfactant protein-B in infants with RSV bronchiolitis was markedly higher than that in matching controls. Our study suggests that alveolocapillary permeability is increased in infants with RSV bronchiolitis in vivo and that surfactant protein-B may be a sensitive marker for lung injury in such infants.
Bronchiolitis, Viral↗
Asthma and respiratory syncytial virus infection in infancy: is there a link?
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Asthma↗
The apoptosis of neutrophils is accelerated in respiratory syncytial virus (RSV)-induced bronchiolitis.
Neutrophils are the predominant inflammatory cell in the lung tissues and airways in RSV infection, and can augment the epithelial cell damage induced by RSV. Neutrophil apoptosis has been suggested to be a mechanism to reduce the potential for tissue injury. The apoptosis of neutrophils from nasopharyngeal aspirates (NPA) (n = 19) and peripheral blood (PB) of infants with RSV bronchiolitis (n = 11) and PB from healthy controls (n = 9) was investigated. Monoclonal antibody against CD95 (Fas) and a binding protein Annexin V were used to determine the apoptosis of neutrophils. The expression of CD11b and CD18 on neutrophils was also detected with flow cytometry. The mean fluorescence intensity (MFI) of CD95 on neutrophils from RSV+ NPA was increased compared with cells from control PB (73.6 +/- 7.6 versus 31.5 +/- 4.3); the MFI of Annexin V, CD11b and CD18 on neutrophils from RSV+ NPA was up-regulated compared with cells from both control PB (105.3 +/- 18.1 versus 11.8 +/- 1.5; 1683 +/- 153.3 versus 841.1 +/- 72.3; 517 +/- 50.5 versus 147 +/- 8.7, respectively) and RSV+ PB (105.3 +/- 18.1 versus 35.8 +/- 4.1; 1683 +/- 153.3 versus 818 +/- 141.2; 517 +/- 50.5 versus 260 +/- 25.8, respectively). Furthermore, the percentage of neutrophils expressing Annexin V and the MFI of CD18 on neutrophils from RSV+ PB were increased compared with neutrophils from control PB. In addition, both CD11b (MFI) and CD18 (MFI) correlated with Annexin V (MFI) on neutrophils. We conclude that neutrophil apoptosis in RSV bronchiolitis is accelerated; and CD11b/CD18 may play an important role in RSV infection by influencing neutrophil apoptosis.
Annexin A5↗
Shedding of L-selectin and PECAM-1 and upregulation of Mac-1 and ICAM-1 on neutrophils in RSV bronchiolitis.
Bronchiolitis is characterized histologically by epithelial necrosis and peribronchial infiltration of leukocytes, with a high percentage of neutrophils in the airways. We investigated the expression of adhesion molecules (CD11a, CD11b, CD18, CD31, CD54, and CD62L) on neutrophils from nasopharyngeal aspirates (NPAs) and peripheral blood (PB) of infants with respiratory syncytial virus (RSV)-induced bronchiolitis. The expression of CD31 and CD62L on neutrophils from NPAs is decreased and the expression of CD11b, CD18, and CD54 on neutrophils from NPAs is increased compared with cells from PB of RSV-infected infants. The expression of CD18 and CD54 on neutrophils from PB of RSV-infected infants is also increased compared with cells from PB of control infants. Shedding of CD31 and CD62L on neutrophils in RSV infection may contribute to the neutrophil emigration from blood to airways; the upregulation of Mac-1 (CD11b/CD18) and CD54 on neutrophils may help explain the high percentage of neutrophils in the airways of RSV bronchiolitis; and the upregulation of Mac-1 may be involved in the increased neutrophil-airway epithelial adhesion in RSV infection.
Antibodies, Monoclonal↗
Neutrophils induce damage to respiratory epithelial cells infected with respiratory syncytial virus.
The mechanisms by which respiratory syncytial virus (RSV) infection induces bronchiolitis and airway disease are unclear. The presence of large numbers of polymorphonuclear leukocytes (PMN) in the airways of infants with RSV infection suggests a potential role of PMN in airway injury associated with RSV infection. To investigate the potential role of neutrophils in RSV bronchiolitis, human alveolar type II cells (A549 cells) were infected with different doses of RSV for 6-48 h. A 51Cr-releasing assay was used to measure PMN-induced damage and image analysis was used to determine PMN adhesion and detachment of epithelial cells. The results showed that RSV infection of epithelial cells enhanced PMN adherence in a dose- and time-dependent pattern, RSV infection alone could damage and detach epithelial cells to a limited extent and PMN significantly augmented RSV infection-induced damage and detachment of epithelial cells. These data suggest that respiratory syncytial virus infection of respiratory epithelial cells enhances neutrophil adhesion to the epithelium and that activated neutrophils augment the damage and detachment of epithelium infected with the virus. Polymorphonuclear leukocytes may contribute to the pathogenesis of respiratory syncytial virus airway disease by inducing epithelial damage and cell loss.
Cell Adhesion↗
Endothelial serpins--protectors of the vasculature?
Vascular damage, initiated by host inflammatory cells, is a component of the pathophysiology of many acute and chronic inflammatory disorders. Neutrophil-mediated tissue damage is mediated primarily by proteinases, particularly elastase and cathepsin G. In this study we have identified endothelial binding of two key serine proteinase inhibitors (serpins), alpha 1-antitrypsin, the inhibitor of elastase, and alpha 1-antichymotrypsin, the inhibitor of cathepsin G. These serpins are shed from the endothelium into the supernatant when neutrophils adherent to the endothelium are activated. Endothelium activated by lipopolysaccharide (LPS) augments this process. Serpin-proteinase complexes activate neutrophils and induce further cytokine release, thereby amplifying inflammatory processes. Strategies aimed at preventing endothelial serpin depletion may help minimize vascular damage during inflammation.
Adult↗
Plasma fibronectin levels in extremely preterm infants in the first 8 weeks of life.
Fibronectin has in the past been considered to function simply as a non-specific plasma opsonin. However, recent studies have demonstrated that this molecule plays an important role in fundamental components of the immune response, for example, neutrophil adhesion, T cell activation and endothelial function. Additionally, fibronectin is important in lung homeostasis where it contributes to alveolar epithelial integrity. In this study plasma fibronectin levels were measured longitudinally in a group of extremely preterm infants, mean gestational age 27 weeks. Plasma fibronectin levels at birth were significantly lower in the preterm study group than in term controls (mean 91 +/- 33 micrograms/mL compared with 214 +/- 62 micrograms/mL in the term controls, P < 0.0001). The preterm cohort demonstrated a more than two-fold rise in plasma fibronectin on days one and two; levels fell almost to baseline values by day three with a subsequent slow rise to a plateau by day 28. No further increase was seen by day 56. This sequence of early changes in fibronectin levels mirrored closely the time course of respiratory distress syndrome. Infants of mothers with pre-eclampsia had significantly lower peak fibronectin levels than in those without (P = 0.016), and those infants with bronchopulmonary dysplasia showed a trend towards lower basal fibronectin levels (P = 0.07) and a greater difference between peak and basal levels (P = 0.05). Neonates, particularly those born preterm, have blunted immunological responses to infection. Fibronectin plays a key role in immunological responsiveness. The significant changes in fibronectin levels after birth in the preterm neonate are likely to have important pathophysiological consequences.(ABSTRACT TRUNCATED AT 250 WORDS)
Age Factors↗
Expression of the leukocyte common antigen CD45 by endothelium.
The CD45 family of Ag expressed by leukocytes play a key role in lymphocyte activation. In this study, we identify both a restricted pattern of expression of CD45 Ag by human endothelial cells and differences in m.w. of endothelial CD45 compared with lymphocyte CD45. Initially, immunoperoxidase staining of endothelial cells in culture revealed the presence of the CD45RO isoform provided the endothelial cells had been stimulated by IL-1 for several days. No other isoform of CD45 was detected by immunoperoxidase staining of endothelium. Leukocyte common antibodies, reputed to detect all isoforms of CD45, did not detect endothelial CD45RO. A polymerase chain reaction method was then used to demonstrate that the message for the CD45RO isoform was constitutively present, with increased levels after IL-1 stimulation. Western blot confirmed the presence of the RO isoform. No other CD45 isoform was detected, either by PCR amplification for message or by Western blot. There were clear differences between lymphocyte and endothelial CD45. The RO isoform expressed by endothelium has an estimated M(r) of 235,000 in contrast to lymphocyte RO that, on our gels, has an estimated M(r) of 190,000. Given the large surface area of endothelium (approximately 1 km2 in the human), the close apposition of lymphocytes and endothelium in immunologic tissues such as lymph nodes, and the pivotal role CD45 plays in activation, expression of CD45RO by endothelium may have important implications in lymphocyte-endothelial interactions. This is most likely to occur in endothelium after a few days of IL-1 stimulation, e.g., at sites of chronic inflammation, or in the draining lymph node of an inflammatory focus.
Actins↗
Wiskott Aldrich syndrome: an immunodeficiency syndrome not rare in Western Australia.
Wiskott Aldrich syndrome, a combined cellular and humoral X-linked immunodeficiency, is generally considered to be rare. The aim of this study was to ascertain the true prevalence in the paediatric population in Western Australia, describe the clinical features, and summarise the current literature on this unusual condition. All cases of Wiskott Aldrich syndrome presenting to Princess Margaret Hospital in Perth during the period from January 1960 to January 1990 were identified by a retrospective review of case records and by interviewing hospital immunology, haematology and general clinical staff. Nine cases of Wiskott Aldrich syndrome are described, demonstrating that the prevalence of Wiskott Aldrich syndrome in Western Australia is nine times that expected from previous reports. Death occurred in a number of patients before the correct diagnosis was recognised. The clinical features in this group are quite variable. Low isohaemagglutinins, elevated IgE, blunted DTH skin multitest, and very low CD8 numbers are however consistent features. Wiskott Aldrich syndrome may be more prevalent than previously recognised, and should be considered in males with thrombocytopenia and infection.
Adolescent↗
Decreased plasma fibronectin concentrations in preterm infants with septicaemia.
Changes in plasma fibronectin concentrations were determined during bacterial septicaemia in extremely preterm infants. The study was a prospective study of fibronectin concentrations in infants of less than 30 weeks' gestation. Concentrations were determined at birth, before sepsis, and throughout the episode of sepsis. Fibronectin concentrations at birth or immediately before sepsis were not significantly different between those infants who developed septicaemia and those who did not (98 (15) v 97 (10) micrograms/ml). In the infants with septicaemia, fibronectin concentrations decreased significantly on day 1 (106 (13) v 173 (18) micrograms/ml for the controls) and remained significantly lower on day 2 (123 (26) v 201 (17) micrograms/ml). By day 5 fibronectin concentrations had increased and were no longer statistically different from controls. Fibronectin is a key modulator of the immune response, with important functions in neutrophil adhesion, bacterial opsonisation, T cell activation, and vascular integrity. Acute depletion of plasma fibronectin during sepsis in preterm neonates may further abrogate their ability to control sepsis.
Bacteremia↗
Assessment of endothelial immunophenotype--limitation of flow cytometric analysis.
Flow cytometry is generally utilized to quantify antigen expression by cells in suspension. To detect antigens on endothelium, which grows as a monolayer, either the creation of a suspension of endothelial cells for flow cytometry, or the use of alternative techniques (such as immunoperoxidase staining) is required. We demonstrate here that creating suspensions of endothelial cells for flow cytometry underestimates the expression of certain antigens. In addition, morphological information regarding certain antigens (serpins and fibronectin) is only discernible by immune microscopy, a subjective procedure. We would recommend caution in using flow cytometry for the estimation of endothelial antigens. Using computerized estimates of microscopic immunostaining (e.g., with video image analysis) it may be possible to overcome some of the subjective limitations of immune microscopy.
Antigens↗
Anti-CD9 antibodies augment neutrophil adherence to endothelium.
Anti-CD9 antibodies which bind to the CD9 (p24) antigen are known to induce platelet and pre-B-cell aggregation. We show here that human endothelium expresses the CD9 antigen, and anti-CD9 antibodies incubated with endothelium induce a rapid increase in adhesion of neutrophils to endothelium by an action on the endothelial cell. This augmented adhesion is not mediated by glycoprotein IIb/IIIa or by the leucocyte integrins. Binding of anti-CD9 antibody to CD9 induces shedding of the CD9/anti-CD9 complex off the endothelial cell in a time-dependent manner. It is likely that CD9 binding to its ligand induces an activation event within the endothelial cell, resulting in surface expression of a pre-formed adhesive ligand for the neutrophil, or an activation change to a constitutively expressed ligand to render it functional.
Antibodies↗