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1.  Bronchial mucosal inflammation and upregulation of CXC chemoattractants and receptors in severe exacerbations of asthma 
Thorax  2007;62(6):475-482.
A study was undertaken to test the hypothesis that severe exacerbations of asthma are characterised by increased bronchial mucosal neutrophilia associated with upregulation of neutrophil chemoattractant ligands and their specific cell surface receptors.
Immunohistology and in situ hybridisation were applied to endobronchial biopsy specimens from three groups: (1) 15 patients admitted to hospital with a severe exacerbation of asthma (E‐asthma), (2) 15 with stable asthma (S‐asthma) and (3) 15 non‐atopic and non‐smoker surgical controls (NSC).
There were significantly more neutrophils and eosinophils in the epithelium and subepithelium of patients in the E‐asthma group (median (range) neutrophils 7 (0–380) and 78 (10–898)/mm2, eosinophils 31 (0–167) and 60 (6–351)/mm2, p⩽0.01 compared with NSC: 0 (0–10, 0–7, 0–18 and 0–3)/mm2, respectively), resulting in similar final densities of eosinophils and neutrophils. With respect to neutrophil chemoattractants and receptors, counts of CXCL5, CXCL8, CXCR1 and CXCR2 mRNA‐positive cells in the subepithelium of the E‐asthma group were, respectively, 5, 4, 4 and 18 times greater (p⩽0.01) than those of the NSC group. In the E‐asthma group, cells expressing CXCL5 or CXCR2 were eightfold and threefold more frequent than those expressing CXCL8 or CXCR1 mRNA, respectively (p<0.01). CXCL5 and CXCR2 in E‐asthma were associated with the number of eosinophils (r = 0.59 and 0.66, p<0.02 for both) rather than the number of neutrophils.
In severe exacerbations of asthma there is a bronchial mucosal neutrophilia, eosinophilia and upregulation of CXC chemoattractants and their receptors. CXCL5 and CXCR2 have an association with eosinophila only, and these represent potentially new targets for treatment in exacerbations of asthma.
PMCID: PMC2117215  PMID: 17234659
2.  Airway Inflammation and Illness Severity in Response to Experimental Rhinovirus Infection in Asthma 
Chest  2014;145(6):1219-1229.
The nature of bronchial mucosal inflammation and its physiologic and clinical significance in rhinovirus-induced asthma exacerbations is unclear. We investigated bronchial mucosal inflammatory response and its association with physiologic and clinical outcomes in an experimental model of rhinovirus-induced asthma exacerbations.
We used immunohistochemistry methods to detect phenotypes of inflammatory cells infiltrating the bronchial mucosa before and after experimental rhinovirus infection in 10 subjects with asthma and 15 normal subjects.
Compared with baseline, rhinovirus infection significantly increased the number of epithelial (P = .005) and subepithelial (P = .017) neutrophils in subjects with asthma only and subepithelial CD68+ macrophages in both subjects with asthma (P = .009) and normal subjects (P = .018) but more so in those with asthma (P = .021). Numbers of CD45+, CD68+, and CD20+ cells; neutrophils; and eosinophils at day 4 postinfection were positively associated with virus load (r = 0.50-0.72, P = .016-0.03). At acute infection in subjects with asthma, CD4+ cells correlated with chest symptom scores (r = 0.69, P = .029), the fall in the 10% fall in FEV1 (PC10) correlated with neutrophils (r = −0.89, P = .029), the PC10 correlated inversely with CD4+ (r = −0.67, P = .023) and CD8+ cells (r = −0.65, P = .03), the 20% fall in FEV1 was inversely associated with CD20+ cells (r = −0.65, P = .03), and higher epithelial CD8+ cell counts were significantly associated with a greater maximum fall in FEV1 (r = −0.72, P = .03), whereas higher subepithelial mast cell counts were significantly associated with a lower maximum percent fall in peak expiratory flow (r = 0.8, P = .024).
In subjects with asthma, rhinovirus infection induces bronchial mucosal neutrophilia and more severe monocyte/macrophage infiltration than in normal subjects. Airway neutrophils, eosinophils, and T and B lymphocytes during infection are related to virus load and physiologic and clinical severity, whereas mast cells are related to greater lung function.
PMCID: PMC4042510  PMID: 24457412
3.  Development of the bronchial epithelial reticular basement membrane: relationship to epithelial height and age 
Thorax  2011;66(4):280-285.
The bronchial epithelium and underlying reticular basement membrane (RBM) have a close spatial and functional inter-relationship and are considered an epithelial–mesenchymal trophic unit (EMTU). An understanding of RBM development is critical to understanding the extent and time of appearance of its abnormal thickening that is characteristic of asthma.
RBM thickness and epithelial height were determined in histological sections of cartilaginous bronchi obtained postmortem from 47 preterm babies and infants (median age 40 weeks gestation (22 weeks gestation–8 months)), 40 children (2 years (1 month–17 years)) and 23 adults (44 (17–90) years) who had died from non-respiratory causes, and had no history of asthma.
The RBM was visible by light microscopy at 30 weeks gestation. RBM thickness increased in successive age groups in childhood; in infants (r=0.63, p<0.001) and in children between 1 month and 17 years (r=0.82, p<0.001). After 18 years, RBM thickness decreased with increasing age (r=−0.42, p<0.05). Epithelial height showed a similar relationship with age, a positive relationship from preterm to 17 years (r = 0.50, p<0.001) and a negative relationship in adulthood (r=−0.84, p<0.0001). There was a direct relationship between epithelial height and RBM thickness (r=0.6, p<0.001).
The RBM in these subjects was microscopically identifiable by 30 weeks gestation. It thickened during childhood and adolescence. In adults, there was either no relationship with age, or a slow reduction in thickness in older age. Developmental changes of RBM thickness were accompanied by similar changes in epithelial height, supporting the close relationship between RBM and epithelium within the EMTU.
PMCID: PMC3471130  PMID: 21233480
4.  Mouse models of rhinovirus-induced disease and exacerbation of allergic airway inflammation 
Nature medicine  2008;14(2):199-204.
Rhinoviruses cause serious morbidity and mortality as the major etiological agents of asthma exacerbations and the common cold. A major obstacle to understanding disease pathogenesis and to the development of effective therapies has been the lack of a small-animal model for rhinovirus infection. Of the 100 known rhinovirus serotypes, 90% (the major group) use human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor and do not bind mouse ICAM-1; the remaining 10% (the minor group) use a member of the low-density lipoprotein receptor family and can bind the mouse counterpart. Here we describe three novel mouse models of rhinovirus infection: minor-group rhinovirus infection of BALB/c mice, major-group rhinovirus infection of transgenic BALB/c mice expressing a mouse-human ICAM-1 chimera and rhinovirus-induced exacerbation of allergic airway inflammation. These models have features similar to those observed in rhinovirus infection in humans, including augmentation of allergic airway inflammation, and will be useful in the development of future therapies for colds and asthma exacerbations.
PMCID: PMC3384678  PMID: 18246079
6.  Co-ordinated Role of TLR3, RIG-I and MDA5 in the Innate Response to Rhinovirus in Bronchial Epithelium 
PLoS Pathogens  2010;6(11):e1001178.
The relative roles of the endosomal TLR3/7/8 versus the intracellular RNA helicases RIG-I and MDA5 in viral infection is much debated. We investigated the roles of each pattern recognition receptor in rhinovirus infection using primary bronchial epithelial cells. TLR3 was constitutively expressed; however, RIG-I and MDA5 were inducible by 8–12 h following rhinovirus infection. Bronchial epithelial tissue from normal volunteers challenged with rhinovirus in vivo exhibited low levels of RIG-I and MDA5 that were increased at day 4 post infection. Inhibition of TLR3, RIG-I and MDA5 by siRNA reduced innate cytokine mRNA, and increased rhinovirus replication. Inhibition of TLR3 and TRIF using siRNA reduced rhinovirus induced RNA helicases. Furthermore, IFNAR1 deficient mice exhibited RIG-I and MDA5 induction early during RV1B infection in an interferon independent manner. Hence anti-viral defense within bronchial epithelium requires co-ordinated recognition of rhinovirus infection, initially via TLR3/TRIF and later via inducible RNA helicases.
Author Summary
Host-pathogen interactions are mediated by pattern recognition receptors that identify conserved structures of micro-organisms that are distinct from self. During a viral infection, important pattern recognition receptors include the endosomal Toll-like receptors (TLRs), and a second set of cytoplasmic pattern recognition receptors known as the RNA helicases. Many studies have highlighted the importance of TLR3, TLR7/8 and the RNA helicases in providing robust anti-viral immunity via interferon induction and inflammation. Both endosomal TLR and cytoplasmic RNA helicase mediated pathways are believed to exist as separate yet non-redundant entities; however, little thought is given to why both systems exist, and few studies also consider how both pathways together contribute to anti-viral immunity. Using models of rhinovirus infection in primary bronchial epithelial cell culture in vitro and experimental infection in mouse and human models in vivo, we show that the RNA helicases are preferentially induced early in the infection cycle via TLR3 mediated signaling events, and work in a co-ordinated, systematic manner. The results help understand the complex events that determine effective innate immunity to rhinovirus infection and how these processes contribute to virus induced exacerbations of asthma and chronic obstructive pulmonary disease.
PMCID: PMC2973831  PMID: 21079690
7.  Allergic rhinitis and asthma: inflammation in a one-airway condition 
BMC Pulmonary Medicine  2006;6(Suppl 1):S5.
Allergic rhinitis and asthma are conditions of airway inflammation that often coexist.
In susceptible individuals, exposure of the nose and lungs to allergen elicits early phase and late phase responses. Contact with antigen by mast cells results in their degranulation, the release of selected mediators, and the subsequent recruitment of other inflammatory cell phenotypes. Additional proinflammatory mediators are released, including histamine, prostaglandins, cysteinyl leukotrienes, proteases, and a variety of cytokines, chemokines, and growth factors. Nasal biopsies in allergic rhinitis demonstrate accumulations of mast cells, eosinophils, and basophils in the epithelium and accumulations of eosinophils in the deeper subepithelium (that is, lamina propria). Examination of bronchial tissue, even in mild asthma, shows lymphocytic inflammation enriched by eosinophils. In severe asthma, the predominant pattern of inflammation changes, with increases in the numbers of neutrophils and, in many, an extension of the changes to involve smaller airways (that is, bronchioli). Structural alterations (that is, remodeling) of bronchi in mild asthma include epithelial fragility and thickening of its reticular basement membrane. With increasing severity of asthma there may be increases in airway smooth muscle mass, vascularity, interstitial collagen, and mucus-secreting glands. Remodeling in the nose is less extensive than that of the lower airways, but the epithelial reticular basement membrane may be slightly but significantly thickened.
Inflammation is a key feature of both allergic rhinitis and asthma. There are therefore potential benefits for application of anti-inflammatory strategies that target both these anatomic sites.
PMCID: PMC1698498  PMID: 17140423
8.  Priming and induction of eosinophil trafficking in guinea-pig cutaneous inflammation by tumour necrosis factor α 
British Journal of Pharmacology  1998;125(6):1228-1235.
Tissue eosinophilia is a hallmark of allergic and parasitic diseases. Priming mechanisms may play an important role in mediating the process of eosinophil accumulation in these conditions. We have previously shown that blockade of tumour necrosis factor α (TNFα) inhibited the capacity of lipopolysaccharide to prime skin sites for chemoattractant-induced eosinophil recruitment. The present study was carried out to investigate the capacity of TNFα to prime an inflammatory site for enhanced eosinophil accumulation.Initial experiments investigated the capacity of TNFα itself to induce eosinophil accumulation. Intradermal injection of murine TNFα (10–300 ng per site) in the guinea-pig induced significant accumulation of 111In-eosinophils. Kinetic studies showed the response to be delayed in onset and inhibited by cycloheximide, consistent with a dependency on protein synthesis. Trafficking of 111In-eosinophils to sites treated for 2 h with TNFα (10–100 ng per site) was inhibited by monoclonal antibodies (mAbs) against β2 or α4 integrins.Intradermal injection of a low dose (3 ng) of TNFα (which by itself had no significant effect on eosinophil trafficking) prior to chemoattractants or antigen in sensitized skin sites, induced significant priming of eosinophil accumulation. Recruitment of both 111In-eosinophils and endogenous eosinophils was enhanced. Trafficking to TNFα-primed responses was dependent on protein synthesis and β2 integrins. In contrast, the α4 integrin mAb failed to inhibit the TNFα primed response.Thus, TNFα can induce and also prime eosinophil recruitment in guinea-pig skin. Our results provide further evidence that this cytokine may be an important mediator of allergic- or parasite-induced eosinophilic inflammation.
PMCID: PMC1565716  PMID: 9863651
Eosinophils; TNFα; inflammation; priming; adhesion molecules
9.  Kinetics of Eotaxin Generation and Its Relationship to Eosinophil Accumulation in Allergic Airways Disease: Analysis in a Guinea Pig Model In Vivo  
Challenge of the airways of sensitized guinea pigs with aerosolized ovalbumin resulted in an early phase of microvascular protein leakage and a delayed phase of eosinophil accumulation in the airway lumen, as measured using bronchoalveolar lavage (BAL). Immunoreactive eotaxin levels rose in airway tissue and BAL fluid to a peak at 6 h falling to low levels by 12 h. Eosinophil numbers in the tissue correlated with eotaxin levels until 6 h but eosinophils persisted until the last measurement time point at 24 h. In contrast, few eosinophils appeared in BAL over the first 12 h, major trafficking through the airway epithelium occurring at 12–24 h when eotaxin levels were low. Constitutive eotaxin was present in BAL fluid. Both constitutive and allergen-induced eosinophil chemoattractant activity in BAL fluid was neutralized by an antibody to eotaxin. Allergen-induced eotaxin appeared to be mainly in airway epithelium and macrophages, as detected by immunostaining. Allergen challenge of the lung resulted in a rapid release of bone marrow eosinophils into the blood. An antibody to IL-5 suppressed bone marrow eosinophil release and lung eosinophilia, without affecting lung eotaxin levels. Thus, IL-5 and eotaxin appear to cooperate in mediating a rapid transfer of eosinophils from the bone marrow to the lung in response to allergen challenge.
PMCID: PMC2199038  PMID: 9254658

Results 1-9 (9)