Luca Spaccapelo

The biology of nitric oxide (NO) has been extensively reviewed. NO was largely regarded as an environmental pollutant until 1987, when its biological similarities to endothelium-derived relaxing factor (EDRF) were noted. Subsequently, NO and EDRF were demonstrated to be identical, modulating vascular tone through stimulated formation of cyclic cAMP. Endogenous NO is formed from L-arginine by one of three (neural, inducible, and endothelial) isoforms of NO synthase, NOS. The physiological role of endogenous NO was first shown when an infusion of an inhibitor of NOS in healthy volunteers led to systemic and pulmonary pressor responses. In 1991, inhaled NO was shown to be a selective pulmonary vasodilator in patients with pulmonary hypertension and in 1993 inhaled NO emerged as a potential therapy for the acute respiratory distress syndrome (ARDS), because it decreases pulmonary vascular resistance without affecting systemic blood pressure and improved oxygenation by redistributing pulmonary blood flow toward ventilated lung units. In patients with acute lung injury and mild pulmonary hypertension, inhaled NO has been associated with a small, short-lived decrease in pulmonary arterial pressure, which has encouraged the use of NO as a supportive treatment for acute right ventricular dysfunction complicating cardiac surgery. Currently, NO is only approved in the US for the treatment of term and near-term (>34 weeks gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hyper-tension in conjunction with ventilatory support where it improves oxygenation and reduces the need for extracorporeal membrane oxygenation. Endogenously produced NO contributes to the control and killing of multiple bacterial species, and while NO is not bactericidal per se, its cytotoxic effect is most likely realized by its reactive nitrogen oxides such as peroxynitrite, to produce potent cytotoxic actions against membrane lipids, nucleic acids, and proteins. In conclusion, several preclinical and clinical studies are providing evidence that the nitrate–nitrite–NO pathway critically subserves physiological hypoxic NO signalling, providing an opportunity for new nitric-oxide-based therapeutics.

Based on a review of the literature regarding the pathophysiology of hypersecretion across various conditions involving respiratory dysfunction, it would appear there are three main underlying causes for excessive sputum production: hypersecretion of mucus glycoprotein and other glandular products from mucus-producing cells, increased transepithelial chloride secretion, mediated via PGE2, PGF2α, TxB2, excessive transudation of plasma proteins into the respiratory tract. These factors may operate independently or in combination. Asthma is characterised by inflammation, increased luminal mucus, with an increased ratio of MUC5B/MUC5AC and MUC2 present in the mucus, epithelial fragility with loss of ciliated cells, goblet cell hyperplasia, submucosal gland hypertrophy, ‘tethering’ of mucus to goblet cells and plasma exudation. COPD and CF have a similar presentation but with a higher MUC5B/MUC5AC ratio and susceptibility to infection. In contrast with the copious sputum production commonly seen in bronchioalveolar carcinoma, bronchorrhoea is not a common feature of CF, asthma, COPD or other conditions with bronchiectasis, where sputum volumes are lower, and the clinical issue may be related more to the viscosity of mucus than to its quantity. Although dramatic positive effects on the BAC-related bronchorrhoea were seen with octreotide and gefitinib treatment, it is therefore doubtful whether agonist of the SST receptor is of clinical usefulness in these other conditions. The reduction in sputum production in BAC seen with both octreotide and gefitinib is likely a result of modu­lation of the EGF receptor, which is known to be involved in goblet cell metaplasia, even if other mechanisms of action cannot be ruled out.  As such, the mechanism of action is potentially relevant also for other pathologies, although currently available EGF-R inhibitors (gefitinib, erlotinib) and somatostatin are perhaps less well adapted for chronic therapy. In conclusion, bronchorrhoea appears to be a sporadic rather than characterising manifestation of asthma, COPD, cystic fibrosis and non-CF bronchiectasis. As a therapeutic target, therefore, bronchorrhoea is not perceived as a high value proposition in these indications, considering existing treatment options and the clinical and regulatory complexities inherent in demonstrating a favourable risk/benefit ratio in a medically plausible subset of patients.