Fibrotic lung diseases, such as idiopathic pulmonary fibrosis, are associated with spontaneous dry cough and hypersensitivity to tussive agents. Understanding the pathophysiology driving enhanced cough may help us to define better therapies for patients. We hypothesized that lung fibrosis induced by intratracheal bleomycin would exacerbate the cough reflex induced by tussive agents in guinea pigs. Disease progression in the lungs was characterized at days 1, 7, 14, 21 and 28 after bleomycin administration. Inflammatory and fibrotic markers, as well as neurotrophin levels, were assessed in bronchoalveolar lavage fluid and/or lung tissue. Cough sensitivity to citric acid, capsaicin and allylisothiocyanate was evaluated in conscious animals at days 14 and 21 after bleomycin administration. Pulmonary lesions evolved from an early inflammatory phase (from day 1 to day 7) to a fibrotic stage (between days 14 and 28). Fibrosis was related to increased levels of matrix metalloproteinase-2 in bronchoalveolar lavage fluid (day 21: saline, 0.26 ng/ml; bleomycin, 0.49 ng/ml). At day 14, we also observed increased cough reflexes to citric acid (163%), capsaicin (125%) and allylisothiocyanate (178%). Cough exacerbation persisted, but at a lower extent, by day 21 for capsaicin (100%) and allylisothiocyanate (54%). Moreover, bronchoalveolar lavage fluid concentrations of brain-derived neurotrophic factor, suggested to induce nerve remodelling in chronic cough, were also enhanced (day 1: saline, 14.21 pg/ml; bleomycin, 30.09 pg/ml). In summary, our model of bleomycin-induced cough exacerbation may be a valuable tool to investigate cough hypersensitivity and develop antitussive therapies for fibrotic lung diseases.

1. Fenspiride is an anti-inflammatory agent that may have a role in reversible obstructive airways disease. Small, but significant, improvements have been seen in airways function and arterial oxygen tension in patients with mild chronic obstructive pulmonary disease. These changes have been attributed to the anti-inflammatory properties of the drug. However, airways function can be improved by other means, e.g. improved ventilation/perfusion ratio or reduced airways resistance. The possibility that fenspiride may have actions other than anti-inflammatory was investigated in two animal species. 2. In the rat, actions on the pulmonary circulation were investigated in the isolated perfused lung, but fenspiride proved to be a poor pulmonary vasodilator, showing only a small reversal of the raised pulmonary artery pressure induced by hypoxia. 3. Ventilation was measured in the anaesthetized rat using whole-body plethysmography. Fenspiride caused no increase in ventilation or changes in arterial blood gases. However, a profound hypotensive action was observed with high doses. 4. The possibility that a decrease in airways resistance ( R aw ) might occur with fenspiride was investigated in anaesthetized guinea pigs. Capsaicin (30 μmol/l) was used to increase baseline R aw through bronchoconstriction. Fenspiride gave a dose-dependent partial reversal of the raised R aw , and its administration by aerosol proved as efficacious as the intravenous route. In addition, the hypotensive side-effect found with intravenous injection was alleviated by aerosolized fenspiride. 5. An anti-bronchoconstrictor action of fenspiride could be one of the mechanisms involved in improving airways function and P ao 2 , seen in mild chronic obstructive pulmonary disease.

1. Mast cell populations in rat lung and spleen were characterized by the presence of two specific protease markers, rat mast cell protease I and II, using both histochemical and radioimmunoassay techniques. Three mast cell populations with different size, morphology and localization were found in lung and spleen and were identified according to the expression of rat mast cell protease I (RMCPI + ) or rat mast cell protease II (RMCPII + ) or of both proteases (RMCPI/II + ). 2. All three mast cell types were in the vicinity of calcitonin-gene-related-peptide-immunoreactive (CGRP + ) nerve fibres in controls as well as in rats infected by Nippostrongylus brasiliensis in which a large increase in the number of both RMCPII + and RMCPI/II + mast cells was found. Ablation of the CGRP + fibres by neonatal treatment with capsaicin resulted in a marked increase in the number of RMCPII + and RMCPI/II + cells in lung and, even more, in spleen of adult rats. 3. The interaction of mast cells with CGRP + C-fibres was assessed pharmacologically by evaluation of the effects of histamine H 3 -receptor ligands known to act on various types of nerve endings, including those of C-fibres. The effects of H 3 -receptor ligands were assessed in controls, nematode-infected rats and neonatally capsaicinized rats. Mast cell activity was evaluated by measurement of [ 3 H]histamine synthesis from [ 3 H]histidine. In control rats, administration of the H 3 -receptor agonist ( R )-α-methylhistamine and antagonist thioperamide, decreased and enhanced respectively [ 3 H]histamine synthesis in lung and spleen, indicating a tonic control of mast cell activity by histamine via H 3 -receptors. Such effects were not found in the jejunum, although RMCPII + mast cells are in close apposition with neuropeptide-containing fibres. The effects of the H 3 -receptor agents were maintained in lung and spleen of nematode-infected rats, but were almost suppressed in capsaicinized rats. 4. It is concluded that the control of mast cells by histamine acting at H 3 -receptors involves neuropeptide-containing nerves and presumably reflects the operation of a local neuron-mast cell feedback loop controlling processes such as ‘neurogenic inflammation’. This loop still functions when mast cells proliferate in an inflammatory condition. These observations suggest that the use of histamine H 3 -receptor agonists may constitute a novel therapeutic approach to limit excessive inflammatory responses resulting from dysregulation of this feedback loop.

1. Twelve non-smoking subjects inhaled capsaicin at three different inspiratory flow rates: 50, 100 and 150 litres/min. Capsaicin was delivered by a breath-actuated dosimeter; inhalations consisted of 0.21–13.6 nmol of capsaicin in doubling amounts given in random order. 2. The mean number of coughs per challenge decreased with increasing inspiratory flow rate. The difference in cough numbers were significant: 7.7 (95% confidence interval 2.5–12.8) for 50 versus 100 litres/min and 10.9 (95% confidence interval 5.0–16.9) for 100 versus 150 litres/min. 3. On a separate day, a cough threshold was measured by giving increasing doses of citric acid that were inhaled at 50 litres/min. There was a positive correlation between the sensitivity to capsaicin and the cough threshold to citric acid ( r = 0.69, P = 0.01), and also between the cough latencies ( r = 0.67, P = 0.02). 4. The negative relationship between the cough response and the inspiratory flow rate may be caused by increased laryngeal deposition at lower inspiratory flow rates. 5. These results are compatible with a similar anatomical distribution of cough receptors for capsaicin and citric acid. 6. These results suggest that changes in inspiratory flow rate may affect the results of cough challenges.

1. The respiratory and cardiovascular effects of capsaicin injection into the superior vena cava and an arm vein were studied in three normal subjects. 2. No changes were seen in tidal volume, inspiratory time or expiratory time after capsaicin injection. Instantaneous heart rate, systolic blood pressure and diastolic blood pressure remained unchanged. 3. Central and peripheral intravenous injections of capsaicin but not control solution above a threshold of 0.5 μg/kg produced dose-dependent sensations sequentially in the chest, face, rectum and extremities. The chest sensation, a ‘raw, burning’ feeling, occurred 3–4 s after central capsaicin injection. No subject reported feeling breathless. In one subject the maximum tolerable dose of capsaicin (4 μg/kg) produced paroxysmal coughing 3.9 s after a central injection. 4. In two of the subjects capsaicin injection was repeated after inhalation of a 5% bupivacaine aerosol (aerodynamic mass median diameter 4.8, μm), sufficient to block the cough reflex to a 5% citric acid aerosol. Prior inhalation of local anaesthetic aerosol abolished the chest sensation after capsaicin injection; the other sensations were unaffected. 5. This study demonstrates that stimulation of receptors accessible from the pulmonary vascular bed does not evoke the pulmonary chemoreflex in conscious man but can produce coughing. It provides evidence for the existence of a nociceptive system of nerve endings in the lung parenchyma that can be blocked by inhaled local anaesthetic aerosol.

1. Substance P, injected into a lateral brain ventricle of urethane-anaesthetized rats, caused dose-dependent increases in blood pressure and heart rate. 2. By contrast, exposure of the obex region of the medulla oblongata to pieces of filter paper soaked in substance P-containing solution resulted in falls of blood pressure and heart rate in both rats and cats. 3. A more precise application of substance P to the first synapse of the baroreceptor reflex by micro-injection into defined areas of the nucleus of the solitary tract also led to an activation of the baroreceptor reflex. 4. Capsaicin, which is known to release substance P from primary afferents, mimicked the sympatho-inhibitory and cardiovascular effects of substance P when applied locally to the nucleus of the solitary tract. 5. The results are compatible with a transmitter or neuromodulatory role for substance P at the first synapse of the baroreceptor reflex.