Harsha H. Kariyawasam

Noninvasive ventilation in cystic fibrosis patients with acute or chronic respiratory failure

The experience of using noninvasive ventilation (NIV) in 113 adult cystic fibrosis (CF) patients with chronic respiratory failure, during episodes of acute deterioration in respiratory function is reported. The patients aged 15–44 yrs were divided into three groups. Group A consisted of 65 patients (median forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) 0.7/1.4 L) who were on a lung transplant waiting list. Group B consisted of 25 patients (median FEV1/FVC 0.7/1.4 L) who were being evaluated for lung transplantation. Group C consisted of 23 patients (median FEV1/FVC 0.6/1.2 L) who were not being considered for lung transplantation. The mean duration of NIV support for groups A, B and C was 61 (range: 1–600) days, 53 (1–279) days and 45 (0.5–379) days respectively. Twenty-three patients in group A subsequently received lung transplantation and 12 of these patients had a median survival of 39 months postsurgery. Thirty-nine patients died and three awaited transplantation. Five patients in group B received a transplant four of whom survived; thirteen patients died and seven awaited transplantation. Twenty patients in group C died. Noninvasive ventilation improved hypoxia but failed to correct hypercapnia in these cystic fibrosis patients. Noninvasive ventilation is useful in the treatment of acute episodes of respiratory failure in cystic fibrosis patients with end-stage lung disease who have been accepted, or are being evaluated, for lung transplantation. For these patients, there is a possibility of prolonging life if they are successfully treated for their acute episode of respiratory failure until transplantation. In this group, treatment is not merely prolonging the process of dying.

Activin-A induces regulatory T cells that suppress T helper cell immune responses and protect from allergic airway disease

Activin-A is a pleiotropic cytokine that participates in developmental, inflammatory, and tissue repair processes. Still, its effects on T helper (Th) cell–mediated immunity, critical for allergic and autoimmune diseases, are elusive. We provide evidence that endogenously produced activin-A suppresses antigen-specific Th2 responses and protects against airway hyperresponsiveness and allergic airway disease in mice. Importantly, we reveal that activin-A exerts suppressive function through induction of antigen-specific regulatory T cells that suppress Th2 responses in vitro and upon transfer in vivo. In fact, activin-A also suppresses Th1-driven responses, pointing to a broader immunoregulatory function. Blockade of interleukin 10 and transforming growth factor β1 reverses activin-A–induced suppression. Remarkably, transfer of activin-A–induced antigen-specific regulatory T cells confers protection against allergic airway disease. This beneficial effect is associated with dramatically decreased maturation of draining lymph node dendritic cells. Therapeutic administration of recombinant activin-A during pulmonary allergen challenge suppresses Th2 responses and protects from allergic disease. Finally, we demonstrate that immune cells infiltrating the lungs from individuals with active allergic asthma, and thus nonregulated inflammatory response, exhibit significantly decreased expression of activin-As responsive elements. Our results uncover activin-A as a novel suppressive factor for Th immunity and a critical controller of allergic airway disease.

Activin and transforming growth factor-β signaling pathways are activated after allergen challenge in mild asthma

BACKGROUND Both transforming growth factor (TGF)-beta(1) and activin-A have been implicated in airway remodeling in asthma, but the modulation of their specific signaling pathways after disease activation remains undefined. OBJECTIVE To define the expression kinetics of TGF-beta(1), activin-A ligands, and follistatin (a natural activin inhibitor), their type I and type II receptors (activin-like kinase[ALK]-1, ALK-5, ALK-4, TbetaRII, and ActRIIA/RIIB) and activation of signaling (via phosphorylated (p) Smad2), in the asthmatic airway after allergen challenge. METHODS Immunohistochemistry was performed on bronchial biopsies from 15 mild atopic patients with asthma (median age, 25 years; median FEV(1)% predicted, 97%) at baseline and 24 hours after allergen inhalation. Functional effects of activin-A were evaluated by using cultured normal human bronchial epithelial (NHBE) cells. RESULTS pSmad2(+) epithelial cells increased at 24 hours (P = .03), and pSmad2 was detected in submucosal cells. No modulation of activin-A, follistatin, or TGF-beta(1) expression was demonstrated. Activin receptor(+) cells increased after allergen challenge: ALK-4 in epithelium (P = .04) and submucosa (P = .04), and ActRIIA in epithelium (P = .01). The TGF-beta receptor ALK-5 expression was minimal in the submucosa at baseline and after challenge and was downregulated in the epithelium after challenge (P = .02), whereas ALK-1 and TbetaRII expression in the submucosa increased after allergen challenge (P = .03 and P = .004, respectively). ALK-1 and ALK-4 expression by T cells was increased after allergen challenge. Activin-A induced NHBE cell proliferation, was produced by NHBE cells in response to TNF-alpha, and downregulated TNF-alpha and IL-13-induced chemokine production by NHBE cells. CONCLUSION Both TGF-beta and activin signaling pathways are activated on allergen provocation in asthma. Activin-A may contribute to resolution of inflammation.

Natural killer T cells in bronchial biopsies from human allergen challenge model of allergic asthma

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IL-25/IL-33-responsive TH2 cells characterize nasal polyps with a default TH17 signature in nasal mucosa.

Background Chronic rhinosinusitis with nasal polyposis (CRSwNP) in Western countries is characterized by eosinophilia, IgE production, and TH2 cytokine expression. Type 2 innate lymphoid cells from polyps produce IL-5 and IL-13 in response to IL-25 and IL-33, although the relevance of this axis to local mucosal T-cell responses is unknown. Objective We sought to investigate the role of the IL-25/IL-33 axis in local mucosal T-cell responses in patients with CRSwNP. Methods Polyp tissue and blood were obtained from patients undergoing nasal polypectomy. Control nasal biopsy specimens and blood were obtained from healthy volunteers. Tissue was cultured in a short-term explant model. T-cell surface phenotype/intracellular cytokines were assessed by means of flow cytometry. T-cell receptor variable β-chain analysis was performed with the immunoSEQ assay. Microarrays were performed for gene expression analysis. Results IL-25 receptor (IL-17RB)–expressing TH2 effector cells were identified in nasal polyp tissue but not the healthy nasal mucosa or periphery. IL-17RB+CD4+ polyp–derived TH2 cells coexpressed ST2 (IL-33 receptor) and responded to IL-25 and IL-33 with enhanced IL-5 and IL-13 production. Within IL-17RB+CD4+ T cells, several identical T-cell receptor variable β-chain complementarity-determining region 3 sequences were identified in different subjects, suggesting clonal expansion driven by a common antigen. Abundant IL-17–producing T cells were observed in both healthy nasal mucosal and polyp populations, with TH17-related genes the most overexpressed compared with peripheral blood T cells. Conclusion IL-25 and IL-33 can interact locally with IL-17RB+ST2+ polyp T cells to augment TH2 responses in patients with CRSwNP. A local TH17 response might be important in healthy nasal mucosal immune homeostasis.

Basal Expression of Bone Morphogenetic Protein Receptor Is Reduced in Mild Asthma

RATIONALE Despite increasing recognition of bone morphogenetic protein (BMP) signaling in tissue remodeling, the expression pattern of ligands and signaling pathways remain undefined in the asthmatic airway. OBJECTIVES To determine expression of BMP ligands (BMP-2, BMP-4, and BMP-7) and type I and type II receptors (ALK-2, ALK-3, ALK-6, and BMPRII) as well as evidence for activation of BMP signaling via detection of phosphorylated Smad1/5 (pSmad1/5) expression in asthmatic airways at baseline (compared with nonasthmatic controls), and after allergen challenge. METHODS Bronchial biopsies were obtained from 6 nonasthmatic control volunteers, and 15 atopic patients with asthma (median age, 25 yr; median FEV(1)% predicted, 97%) at baseline, then at 24 hours and 7 days after allergen challenge. Expression of BMP ligands, receptors, and signaling was analyzed using immunohistochemistry. MEASUREMENTS AND MAIN RESULTS BMP ligand expression did not differ between asthmatic and control airways at baseline. Compared with the normal airway, there was significant down-regulation of ALK-2 (P = 0.001), ALK-6 (P = 0.0009), and BMPRII (P = 0.009) expression in asthma. Allergen challenge was associated with marked and sustained up-regulation of BMP-7 in airway epithelium (P = 0.017) and infiltrating inflammatory cells (P = 0.071) (predominantly in eosinophils, but also CD4(+) T cells, mast cells, and macrophages). Up-regulation of pSmad1/5 expression (P = 0.031), ALK-2 (P = 0.002), and ALK-6 (P < 0.001) was observed indicating active signaling. CONCLUSIONS BMP receptor expression is down-regulated in the asthmatic airway, which may impede repair responses. Allergen provocation increases expression of the regulatory ligand BMP-7, activates BMP signaling, and increases receptor expression, all of which may contribute to repair and control of inflammation.

Activin‐A: a novel critical regulator of allergic asthma

Activin‐A is a pleiotropic cytokine that belongs to the TGF‐β superfamily and plays an important role in fundamental biological processes, such as development and tissue repair. Growing evidence proposes a crucial role for activin‐A in immune‐mediated responses and associated diseases, with both enhancing and suppressive effects depending on the cell type, the cytokine micromilieu and the context of the response. Several recent studies have demonstrated a striking increase in activin‐A expression in experimental models of asthma, as well as, in the asthmatic airway in humans. Importantly, a strong immunoregulatory role for activin‐A in allergic airway disease, with suppression of T helper (Th) type 2 cell‐driven allergic responses and protection against the development of cardinal features of the asthmatic phenotype was revealed by in vivo functional studies. Activin‐A‐mediated immunosuppression is associated with induction of functional allergen‐specific regulatory T cells. In human asthma, although activin‐A levels are increased in the airway epithelium and submucosal cells, the expression of its signalling components is markedly decreased, pointing to decreased regulation. Nevertheless, a rapid activation of the activin‐A signalling pathway is observed in the airway of individuals with asthma following inhalational allergen challenge, suggestive of an inherent protective mechanism to control disease. In support, in vitro studies using human airway epithelial cells have demonstrated that endogenous activin‐A suppresses the release of inflammatory mediators, while it induces epithelial repair. Collectively, compelling evidence suggests that activin‐A orchestrates the regulation of key events involved in the pathogenesis of allergic asthma. The critical role of activin‐A in allergic airway responses places this cytokine as an exciting new therapeutic target for asthma.

Altered sialyl- and fucosyl-linkage on mucins in cystic fibrosis patients promotes formation of the sialyl-Lewis X determinant on salivary MUC-5B and MUC-7.

Abstract. Destruction of the lungs as a consequence of recurrent infections with microorganisms such as Pseudomonasaeruginosa remains the underlying cause of most morbidity and mortality in cystic fibrosis (CF). We have hypothesized that changes in the glycosylation of key tracheal mucins such as MUC5B and MUC7 might increase the risk of pulmonary disease in CF patients. However, in preference to sputum we have examined the sugar-chains on these mucins in saliva because in the latter not only can the glycoproteins be collected from controls, but they are essentially free from modifications made following bacterial infection in disease. Proteins in ductal or whole-mouth saliva from 20 CF patients with the ΔF-508CFTR mutation and age-and sex-matched controls were separated by SDS-PAGE and blotted onto nitrocellulose and then probed with labelled lectins of known specificity. Linkage of terminal sialic acid on the blotted mucins was determined using Sambucusnigra agglutinin (detects the 2→6 linkage) and Maackiaamurensis agglutinin (the 2→3 linkage). Fucose was detected by Ulexeuropaeus agglutinin-1 (1→2 linkage) and Aleuriaaurantia agglutinin (1→3 linkage). We found that each mucin shows a characteristic glycosylation pattern and in controls most of the sialic acid is 2→6 linked on MG1 (MUC 5B) and 2→3 linked on MG2 (MUC 7). CF is associated with a shift from a 2→6 linkage to a 2→3 linkage on MG1 with some patients showing almost no 2→6 linkage; 2→3 linkage on MG2 is similarly increased in disease in some individuals. The expression of fucose on these mucins is also raised in CF patients. These shift to a 2→3 linkage of sialic acid, and with increased fucosylation this promotes the formation of sialyl-Lewis X antigen detected on CF mucins in our study. These changes will be tested for their correlation with the severity of lung disease. We gratefully acknowledge support from the European Union Biomed-II Programme.

Airway remodelling in asthma: models and supermodels?

Although currently anti-inflammatory treatments are effective for most of the 5 million patients treated in the UK they do not completely control symptoms, and a minority of asthmatics continue to experience severe debilitating disease [1]. Of note, although inhaled corticosteroids reduce the Th2type eosinophilic airway inflammation and airway hyperresponsiveness (AHR) that characterize asthma, they do not restore either variable to normal [2]. For this reason attention has been focused on structural changes in the asthmatic airway termed airway remodelling. These changes include epithelial damage and goblet cell hyperplasia [3], increased airway smooth muscle [4] and recruitment and activation of myofibroblasts [5]. Increased deposition of collagens and other extracellular matrix proteins such as tenascin and fibronectin occurs both in the reticular basement membrane (RBM) [6] and throughout the bronchial mucosa and this structural remodelling is accompanied by new blood vessel formation [7]. The clinical consequences of airway remodelling in asthma remain uncertain but contributions to AHR and fixed airflow obstruction have been suggested. Mathematical modelling predicts that airways with increased smooth muscle narrow to a much greater extent than airways with less smooth muscle volume for a given degree of circumferential smooth muscle shortening [8]. Asthmatic subjects show accelerated decline in lung function over time compared with non-asthmatic subjects, and this loss of lung function is more marked in asthmatic smokers [9, 10]. Although duration and severity of asthma are the most important risk factors for development of fixed obstruction the highest rate of loss of lung function is seen during the early course of the illness. Interestingly, remodelling changes are seen early in childhood and may even pre-date the onset of symptoms [11]. The impact of current anti-inflammatory treatment on remodelling is controversial. Although partial reversal of remodelling has been reported with inhaled corticosteroid treatment, responses are seen after prolonged therapy [12] and are not confirmed in all studies. The initial rapid improvement in AHR in asthma with inhaled corticosteroid treatment may be explained by reduction in airway inflammation [13], but additional improvements over many months may reflect changes in remodelling. Important questions about airway remodelling in asthma remain unanswered (see Fig. 1). These include:

Anaemia in lung transplant patient caused by parvovirus B19

The case history is presented of a lung transplant patient who developed prolonged parvovirus B19 infection with severe transfusion dependent anaemia. The patient was treated with intravenous immunoglobulin after which the haemoglobin rose, together with a reticulocytosis. The patient then remained transfusion free and the virus cleared more than three months after the initial immunoglobulin treatment. The clinical and social implications for this group of patients are discussed.