Neville Berkman

The effect of treatment with omalizumab, an anti-IgE antibody, on asthma exacerbations and emergency medical visits in patients with severe persistent asthma.

Background:  Patients with severe persistent asthma who are inadequately controlled despite treatment according to current asthma management guidelines have a significant unmet medical need. Such patients are at high risk of serious exacerbations and asthma‐related mortality.

Exhaled nitric oxide in the diagnosis of asthma: comparison with bronchial provocation tests.

Background: Bronchial provocation tests such as exercise, methacholine (MCH), and adenosine-5′-monophosphate (AMP) challenges are used extensively in the diagnosis of asthma. A study was undertaken to determine whether exhaled nitric oxide (eNO) can be used to diagnose asthma in patients with non-specific respiratory symptoms and to compare this test with conventional provocation tests. Methods: Patients with non-specific respiratory symptoms and normal spirometric parameters were included in the study. eNO was measured and exercise, MCH and AMP challenges performed in all subjects. Patients were defined as asthmatic based on clinical follow up 24 months after testing. Results: Forty patients were considered asthmatic and 45 were not. The area under receiver operating characteristic curves gave values of 0.896 for eNO, 0.781 for exercise, 0.924 for MCH, and 0.939 for AMP (p = 0.033, 0.575 and 0.085 for eNO v exercise, MCH and AMP respectively). From our data, a cut off value of NO >7 ppb at a flow rate of 250 ml/s best differentiates between asthmatics and non-asthmatics (sensitivity 82.5%, specificity 88.9%). Optimal cut off values for other tests were exercise: ΔFEV1 ⩾10% (sensitivity 57.9%, specificity 100%); PC20-MCH: ⩽3 mg/ml (sensitivity 87.5%, specificity 86.7%); and PC20-AMP: ⩽150 mg/ml (sensitivity 89.5%, specificity 95.6%). Conclusions: Measurement of eNO can be used as a safe, simple and rapid test for the diagnosis of asthma and is as good as bronchial provocation tests.

Pulmonary involvement in lymphoma

Intrathoracic involvement is common in both Hodgkins disease (HD) and non-Hodgkins lymphoma (NHL). The most common manifestation is mediastinal lymphadenopathy. In HD, nodal involvement is by contiguity and usually involves the superior mediastinum, while the findings in NHL are more variable. Pulmonary parenchymal disease occurs in 38% of HD and 24% of NHL. In untreated HD, parenchymal involvement is invariably associated with mediastinal lymphadenopathy and often with widespread disease. Three distinct radiological patterns of pulmonary lymphoma are recognised: nodular, bronchovascular-lymphangitic and pneumonic-alveolar. Rarely lymphoma may be endobronchial. Pleural effusion occurs in 16% of lymphoma patients and is usually associated with disease elsewhere. It is frequently caused by lymphatic obstruction but may be due to direct pleural involvement by tumour. Chylothorax may occur in NHL but is unusual in HD. Diagnosis of intrathoracic lymphoma is by transbronchial or transthoracic biopsy or by needle aspiration of tissue or pleural fluid. The addition of immunostaining improves the diagnostic yield in equivocal cases. Treatment and prognosis vary depending on cell-type, location and extent of disease.

EDA-containing cellular fibronectin induces fibroblast differentiation through binding to α4β7 integrin receptor and MAPK/Erk 1/2-dependent signaling

Fibroblast differentiation is an essential step during wound healing and fibrosis. Fibronectin (FN) is a major component of the extracellular matrix and occurs in two main forms: plasma and cellular FN. The latter includes the alternatively spliced domain A (EDA). Although EDA‐containing cellular fibronectin (EDA‐FN) is associated with fibroblast differentiation, how EDA‐FN promotes differentiation is incompletely understood. In this study, we investigate the mechanism by which EDA‐FN contributes to fibroblast differentiation with emphasis on the characterization of the EDA‐FN receptor. We show that EDA‐FN increases α‐SMA expression (immunofluorescence), collagen deposition, cell contractility, and focal adhesion kinase (FAK) activation (immunoblotting); whereas plasma FN, a form lacking EDA, shows no effect. Primary lung fibroblasts constitutively express α4β7 integrin receptor (FACS and RT‐PCR). Blocking of α4β7 reduces fibroblast adhesion to EDA‐FN and inhibits α‐SMA expression, collagen deposition, and FAK activation induced by EDA‐FN. Using recombinant EDA‐containing peptides, we demonstrate that the EDA segment is sufficient to induce fibroblast differentiation via binding to α4β7. EDA‐FN induces MAPK‐Erk1/2 activation and inhibition of MEK1/2 attenuates EDA‐FN‐induced α‐SMA expression. Our findings demonstrate that EDA‐FN induces fibroblast differentiation by a mechanism that involves binding of EDA to α4β7 integrin followed by activation of FAK and MAPK‐associated signaling pathways.— Kohan, M., Muro, A. F., White, E. S., Berkman, N. EDA‐containing cellular fibronectin induces fibroblast differentiation through binding to α4β7 integrin receptor and MAPK/Erk 1/2‐dependent signaling. FASEB J. 24, 4503–4512 (2010). www.fasebj.org

Pulmonary complications of bone marrow transplantation

Over the last couple of decades, bone marrow transplantation (BMT) has become the therapy of choice for a number of malignant and non-malignant haematologic and non-haematologic disorders. The number of diseases in which BMT has been tried with a reasonable degree of success is ever-increasing. In addition, autologous and partially compatible allogeneic BMTs are being performed successfully. These factors have contributed to an expanding therapeutic application of BMT. The technique is potentially curative for patients with acute lymphoblastic and non-lymphoblastic leukaemias, chronic myelogenous leukaemia, malignant lymphomas, multiple myeloma, severe aplastic anaemia, severe combined immunodeficiency disorders, thalassemia major, and other selected non-haematologic disorders (Tables 1, 2). Disease-free survival after the fourth year postallogeneic BMT occurs in 55% of patients with first remission of acute non-lymphoblastic leukaemia and in 83% of patients with non-transfused severe aplastic anaemia. Despite these encouraging results, several transplantation-related complications prevent further improvement of survival rates. Most prominent among these are pulmonary complications and graft-versus-host disease (GVHD). Pulmonary complications of bone marrow transplantation are diverse and account for significant morbidity and mortality (1-6). More than 30% of transplantation-related deaths are attributed to respiratory disorders. Pulmonary complications are classified as early or late, depending on whether they occur before or after 100 days post-transplantation (Table 3).

Osteopontin Induces Airway Remodeling and Lung Fibroblast Activation in a Murine Model of Asthma

Airway remodeling is a central feature of asthma; however, the mechanisms underlying its development have not been fully elucidated. We have demonstrated that osteopontin, an inflammatory cytokine and an extracellular matrix glycoprotein with profibrotic properties, is up-regulated in a murine model of allergen-induced airway remodeling. In the present study, we determined whether osteopontin plays a functional role in airway remodeling. Osteopontin (OPN)-deficient (OPN(-/-)) and wild-type mice were sensitized and exposed to inhaled ovalbumin (OVA) or saline for 5 weeks. Collagen production, peribronchial smooth muscle area, mucus-producing cell number, and bronchoalveolar cell counts were assessed. The functional behavior and phenotype of lung fibroblasts from OVA-treated OPN(-/-) and from wild-type mice were studied using ex vivo cultures. OVA-treated OPN(-/-) mice exhibited reduced lung collagen content, smooth muscle area, mucus-producing cells, and inflammatory cell accumulation as compared with wild-type mice. Reduced matrix metalloproteinase-2 activity and expression of transforming growth factor-beta1 and vascular endothelial growth factor were observed in OVA-treated OPN(-/-) mice. Lung fibroblasts from OVA-treated OPN(-/-) mice showed reduced proliferation, migration, collagen deposition, and alpha-smooth muscle actin expression in comparison with OVA-treated wild-type lung fibroblasts. Thus, OPN is key for the development of allergen-induced airway remodeling in mice. In response to allergen, OPN induces the switching of lung fibroblasts to a pro-fibrogenic myofibroblast phenotype.

Use of Fiberoptic Bronchoscopy in Bone Marrow Transplant Recipients

Bone marrow transplantation (BMT) has become the therapy of choice for a number of malignant and nonmalignant hematologic and nonhematologic disorders. A frequent complication after BMT is pulmonary disease which is associated with a high mortality rate. We examined the results of 79 bronchoscopies performed between May 1991 and May 1995 in 62 patients for the evaluation of pulmonary complications after BMT. In all cases bronchoalveolar lavage (BAL) was performed, in 10% transbronchial biopsy (TBB) was also carried out and in 13% bronchoscopy was followed by open lung biopsy. Positive results were found in 67% of bronchoscopies. Fungal infection (Candida and Aspergillus species) was the most common finding (18%), bacterial infection was found in 13%, mixed (fungal and bacterial) infection in 6%, cytomegalovirus in 11% and Pneumocystis carinii pneumonia in 4%. Diffuse alveolar hemorrhage was detected in 11% of cases. Idiopathic pneumonia syndrome (IPS) was diagnosed by TBB in 3% of procedures. We conclude that BAL is a safe and accurate procedure for the evaluation of pulmonary complications after BMT. TBB should be considered in the absence of thrombocytopenia for the diagnosis of IPS. If bronchoscopy findings are negative, open lung biopsy should be considered.

Enhanced osteopontin expression in a murine model of allergen-induced airway remodelling.

Background Airway remodelling is a central pathophysiological feature of chronic asthma. A wide variety of cytokines and growth factors are likely to be involved in the development of airway remodelling. Osteopontin (OPN) is a cytokine with pro‐fibrotic properties; however, its role in airway remodelling in asthma has not been explored.

Osteopontin is expressed and functional in human eosinophils.

To cite this article: Puxeddu I, Berkman N, Ribatti D, Bader R, Haitchi HM, Davies DE, Howarth PH, Levi‐Schaffer F. Osteopontin is expressed and functional in human eosinophils. Allergy 2010; 65: 168–174.

The role of eosinophil major basic protein in angiogenesis

Background:  Eosinophil‐derived major basic protein (MBP) plays an active role in allergic inflammation and tissue remodelling. However, its role in angiogenesis has not been established as yet. Therefore our objective was to investigate whether MBP exhibits any direct pro‐angiogenic effects.