Terence M. O'Connor

The Role of Substance P in Inflammatory Disease

The diffuse neuroendocrine system consists of specialised endocrine cells and peptidergic nerves and is present in all organs of the body. Substance P (SP) is secreted by nerves and inflammatory cells such as macrophages, eosinophils, lymphocytes, and dendritic cells and acts by binding to the neurokinin‐1 receptor (NK‐1R). SP has proinflammatory effects in immune and epithelial cells and participates in inflammatory diseases of the respiratory, gastrointestinal, and musculoskeletal systems. Many substances induce neuropeptide release from sensory nerves in the lung, including allergen, histamine, prostaglandins, and leukotrienes. Patients with asthma are hyperresponsive to SP and NK‐1R expression is increased in their bronchi. Neurogenic inflammation also participates in virus‐associated respiratory infection, non‐productive cough, allergic rhinitis, and sarcoidosis. SP regulates smooth muscle contractility, epithelial ion transport, vascular permeability, and immune function in the gastrointestinal tract. Elevated levels of SP and upregulated NK‐1R expression have been reported in the rectum and colon of patients with inflammatory bowel disease (IBD), and correlate with disease activity. Increased levels of SP are found in the synovial fluid and serum of patients with rheumatoid arthritis (RA) and NK‐1R mRNA is upregulated in RA synoviocytes. Glucocorticoids may attenuate neurogenic inflammation by decreasing NK‐1R expression in epithelial and inflammatory cells and increasing production of neutral endopeptidase (NEP), an enzyme that degrades SP. Preventing the proinflammatory effects of SP using tachykinin receptor antagonists may have therapeutic potential in inflammatory diseases such as asthma, sarcoidosis, chronic bronchitis, IBD, and RA. In this paper, we review the role that SP plays in inflammatory disease. J. Cell. Physiol. 201: 167–180, 2004.

Effects of budesonide and formoterol on allergen-induced airway responses, inflammation, and airway remodeling in asthma

BACKGROUND Combining inhaled corticosteroids with long-acting beta(2)-agonists results in improved asthma symptom control and fewer asthma exacerbations compared with those seen after inhaled corticosteroids alone. However, there are limited data as to whether these beneficial effects are due to enhanced anti-inflammatory actions or whether such combination therapies affect airway remodeling in patients with asthma. OBJECTIVE We sought to determine the effects of inhaled budesonide/formoterol combination therapy versus inhaled budesonide alone or inhaled placebo on allergen-induced airway responses, airway inflammation, and airway remodeling. METHODS Fourteen asthmatic subjects with dual responses after allergen inhalation were included in this prospective, randomized, double-blind, 3-period crossover study. Outcomes included early and late asthmatic responses, changes in airway responsiveness, sputum eosinophilia measured before and after allergen challenge, numbers of airway submucosal myofibroblasts, and smooth muscle area measured before and after study treatment. RESULTS Allergen-induced sputum eosinophilia was significantly reduced by combination treatment to a greater extent than by budesonide alone. Allergen inhalation resulted in a significant increase in submucosal tissue myofibroblast numbers and produced a significant decrease in percentage smooth muscle area. Combination therapy, but not budesonide monotherapy, significantly attenuated these changes in myofibroblast numbers and smooth muscle area. CONCLUSIONS The effects on allergen-induced changes in sputum eosinophils, airway myofibroblast numbers, and smooth muscle seen with combination therapy suggest that the benefits associated with this treatment might relate to effects on airway inflammation and remodeling. The attenuation of early asthmatic responses and airway hyperresponsiveness by combination treatment was likely due to the known functional antagonistic effect of formoterol.

Type 1 diabetes mellitus, coeliac disease, and lymphoma: a report of four cases

Introduction Patients with Type 1 diabetes mellitus have a high prevalence of coeliac disease, symptoms of which are often mild, atypical, or absent. Untreated coeliac disease is associated with an increased risk of malignancy, particularly of lymphoma. We describe four patients with Type 1 diabetes mellitus and coeliac disease who developed lymphoma.

Upregulation of neurokinin-1 receptor expression in the lungs of patients with sarcoidosis.

Substance P (SP) is a proinflammatory neuropeptide that is secreted by sensory nerves and inflammatory cells. Increased levels of SP are found in sarcoid bronchoalveolar lavage fluid. SP acts by binding to the neurokinin-1 receptor and increases secretion of tumor necrosis factor-α in many cell types. We sought to determine neurokinin-1 receptor expression in patients with sarcoidosis compared with normal controls. Neurokinin-1 receptor messenger RNA and protein expression were below the limits of detection by reverse transcriptase-polymerase chain reaction and immunohistochemistry in peripheral blood mononuclear cells of healthy volunteers (n = 9) or patients with stage 1 or 2 pulmonary sarcoidosis (n = 10), but were detected in 1/9 bronchoalveolar lavage cells of controls compared with 8/10 patients with sarcoidosis (p = 0.012) and 2/9 biopsies of controls compared with 9/10 patients with sarcoidosis (p = 0.013). Immunohistochemistry localized upregulated neurokinin-1 receptor expression to bronchial and alveolar epithelial cells, macrophages, lymphocytes, and sarcoid granulomas. The patient in whom neurokinin-1 receptor was not detected was taking corticosteroids. Incubation of the type II alveolar and bronchial epithelial cell lines A549 and SK-LU 1 with dexamethasone downregulated neurokinin-1 receptor expression. Upregulated neurokinin-1 receptor expression in patients with sarcoidosis may potentiate substance P-induced proinflammatory cytokine production in patients with sarcoidosis.

Allergic bronchopulmonary aspergillosis: A rare cause of pleural effusion

Aspergillus fumigatus is one of the most ubiquitous of the airborne saprophytic fungi. Allergic bronchopulmonary aspergillosis (ABPA) is a syndrome seen in patients with asthma and cystic fibrosis, and is characterized by hypersensitivity to chronic colonization of the airways with A. fumigatus. We report the case of a patient with ABPA presenting with pleural effusion. A 27‐year‐old male was referred with recurrent right pleural effusion. Past medical history was remarkable for asthma, allergic sinusitis, and recurrent pleurisy. Investigations revealed peripheral eosinophilia with elevated serum immunoglobulin E and bilateral pleural effusions with bilateral upper lobe proximal bronchiectasis. Precipitating serum antibodies to A. fumigatus were positive and the A. fumigatus immediate skin test yielded a positive reaction. A diagnosis of ABPA associated with bilateral pleural effusions was made and the patient was commenced on prednisolone. At review, the patient’s symptoms had considerably improved and his pleural effusions had resolved. ABPA may present with diverse atypical syndromes, including paratracheal and hilar adenopathy, obstructive lung collapse, pneumothorax and bronchopleural fistula, and allergic sinusitis. Allergic bronchopulmonary aspergillosis is a rare cause of pleural effusion and must be considered in the differential diagnosis of patients presenting with a pleural effusion, in particular those with a history of asthma.

Rare causes of persistent wheeze that mimic poorly controlled asthma

Upper airway obstruction can present with stridor or expiratory or inspiratory wheeze and is commonly misdiagnosed as asthma. As asthma is common, such cases can remain hidden among patients with lower airway obstruction who attend primary care or respiratory clinics. We describe four causes of upper airway obstruction (paradoxical vocal cord movement, subglottic stenosis, retrosternal goitre and double aortic arch) which were misdiagnosed as ‘poorly controlled asthma’.

Airways obstruction in survivors of thoracoplasty: reversibility is greater in non-smokers.

Objective:  Before the advent of antituberculous chemotherapy, thoracoplasty (TPL) was the definitive form of therapy for cavitary pulmonary tuberculosis. This study aimed to characterize the late functional sequelae of TPL, and to establish the degree of reversibility of any consequent airway obstruction.

Holy Saturday asthma

A 61-year-old man complained of cough and dyspnoea after exposure to colophony-containing solder fumes at work. A histamine challenge test confirmed airway hyper-responsiveness, and colophony-challenge demonstrated a 16.7% drop in peak expiratory flow rate (PEFR), supporting a diagnosis of colophony-induced occupational asthma. At review, the patient presented with cough, dyspnoea and wheeze that occurred acutely when exposed to the fumes from burning incense during Easter Saturday services, necessitating his departure from the church. Inhalation challenge tests using two blends of incense used at his church (Greek and Vatican) led to identical symptoms and a significant reduction in forced expiratory volume in 1 s 15 min after exposure and PEFRs up to 48 h after exposure, indicating an early and late phase asthmatic reaction. This is the first report of coexistent colophony and incense-induced asthma. The similarities in chemical structures between abietic acid in colophony and boswellic acid in incense suggest a common mechanism.

A case series of patients on chemotherapy with dyspnoea and pulmonary infiltrates

Clinicians often assume that patients who develop pulmonary symptoms and radiographic infiltrates while receiving cytotoxic chemotherapy have opportunistic pulmonary infection or chemotherapy-related interstitial lung disease. We describe two cases of rare complications of commonly used chemotherapeutic agents (gemcitabine-induced eosinophilic pneumonia and rituximab-induced hypersensitivity pneumonitis) that vindicate this assumption but a third case of scleroderma-associated interstitial lung disease that became clinically manifest in a patient who was receiving chemotherapy. The latter case highlights the need for vigilance for other causes of interstitial lung disease in patients receiving chemotherapy.

Bilateral Chylothorax Secondary to Retrosternal Goitre: a Case Report and Review of the Literature

Chylothorax is characterized by an accumulation of lymphatic fluid in the pleural cavity due to damage to the thoracic duct. The aetiology can be traumatic or non-traumatic. Goitre is a rare cause of chylothorax with only eight cases previously described in the literature including only one case causing a bilateral chylothorax. This report describes a patient with bilateral chylothorax secondary to substernal goitre, which was successfully treated, and discusses this very rare case in light of the available literature. LEARNING POINTS Pleural ultrasound and aspiration is important in bilateral pleural effusions unresponsive to diuretic treatment, or of dubious origin. The aetiology, diagnosis and treatment of a chylothorax are described. Goitre can cause chylothorax by damaging the thoracic duct.