Streptococcus pneumoniae infections are common, but how they cause host tissue injury and death is incompletely understood. Immunization with pneumolysin, a thiol-activated toxin produced by the pneumococcus, partially protects animals during subsequent infection. The mechanism by which pneumolysin contributes to disease is not known. The aim of the present investigation was to determine the histologic changes induced by recombinant pneumolysin in the rat lung and to compare them with the changes induced by live organisms. Injection of either toxin (200 or 800 ng) or bacteria into the apical lobe bronchus was associated with the development of a severe lobar pneumonia restricted to the apical lobe. The changes induced by the toxin were greater at the higher concentration, and changes were most severe in those animals in which there was partial ligation of the apical lobe bronchus. The pneumonitis was less severe following injection of a modified toxin with decreased hemolytic activity, generated by site-directed mutagenesis of the cloned pneumolysin gene, indicating that this property of the toxin was important in generating pulmonary inflammation. There was still considerable pneumonitis after injection of a modified toxin with decreased capacity to activate complement.

SUMMARY1. We studied the effect of capsaicin and sensory neuropeptides on tracheal goblet cell secretion in anaesthetized guinea-pigs using a semi-quantitative morphometric technique whereby the magnitude of discharge of stained intracellular mucus, expressed as a mucus score (MS), was related inversely to discharge.2. Capsaicin (I.v.) induced goblet cell secretion: a decrease of 50% in MS below control (indicative of increased secretion) was maximal at 3-3 x 10-1 mol/kg.3. Capsaicin-induced secretion was unaffected either by prior vagus nerve section or by pre-treatment with atropine, propranolol and phentolamine which suggests that local axon reflexes with release of sensory neuropeptides are involved in the response.4. Intravenous substance P (SP), neurokinin A (NKA), neurokinin B (NKB), and calcitonin gene-related peptide (CGRP) produced dose-related increases in goblet cell secretion, with SP the most potent. Doses (mol/kg) causing a 50% decrease in MS from control were 3-5 x 0-12 for SP; 72 x 10"1 for NKA; 1-6 x 10-9 for NKB; and 1-2 x 10-8 for CGRP. The maximal increase in goblet cell secretion was 75% of control and occurred with SP at 10-10 mol/kg. 5. SP-induced mucus discharge was not inhibited by atropine or the histamine receptor antagonists mepyramine or cimetadine. 6. We conclude that in guinea-pig trachea, goblet cell secretion is under the control of capsaicin-sensitive sensory nerves and release of neuropeptides from these nerves may induce mucus discharge via tachykinin receptors of the NK-1 subtype (indicated by an order of potency of SP > NKA > NKB).

We studied the neural control of goblet cell secretion in the lower airways of anesthetized guinea pigs using a semiquantitative morphometric technique. The magnitude of discharge of intracellular mucus was determined in histological sections of the trachea and main bronchi stained for mucus glycoproteins. Bilateral electrical stimulation of the cervical vagus nerves induced goblet cell secretion. The magnitude of the effect was dependent on the frequency, voltage, and pulse width of the stimulus, and the duration of stimulation. At 10 Hz, 5 V, and 5 ms for 3 min, there was a 62% decrease in the amount of intracellular mucus below that with sham stimulation. The secretion was blocked either by atropine or by pretreatment with capsaicin but was not significantly inhibited by idazoxan, an alpha-adrenoceptor antagonist. The magnitude of goblet cell discharge in animals pretreated with propranolol was intermediate between that in controls and that with nerve stimulation, although not significant to either. These results demonstrate that goblet cell secretion is under neural control in guinea pig airways and suggest that cholinergic, nonadrenergic-noncholinergic, and possibly adrenergic neural pathways, may contribute to the secretion.

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1 Nonadrenergic, noncholinergic (NANC) nerves mediate vasodilatation in guinea-pig pulmonary artery (PA) by both endothelium-dependent and endothelium-independent mechanisms. The transmitter(s) involved in the endothelium-independent pathway have not yet been identified. We have therefore investigated the possibility that nitric oxide (NO) and guanosine 3',5'-cyclic monophosphate (cyclic GMP) may mediate this neural vasodilator response in guinea-pig branch PA rings denuded of endothelium. 2 Electric field stimulation (EFS, 50 V, 0.2 ms) induced a frequency-dependent (1-24 Hz), tetrodotoxin-sensitive relaxation of the U44069-precontracted PA rings in the presence of adrenergic and cholinergic blockade. 3 The NO synthase inhibitors NG-monomethyl L-arginine (L-NMMA, 100 pM) and NG-nitro L-arginine methyl ester (L-NAME, 30 pM), and the guanylyl cyclase inhibitor methylene blue (5 pM) inhibited the EFS (16 Hz)-induced relaxation by 53 ± 5, 74 + 9 and 82 ± 9% respectively (n = 5-7, P<0.01, compared with control rings).4 Excess concentrations of L-, but not D-arginine (300 gM) completely reversed the inhibitory effect of L-NMMA. 5 The EFS-elicited relaxation (4 Hz) was potentiated by 1 gM zaprinast, a type V phosphodiesterase inhibitor which inhibits guanosine 3':5'-cyclic monophosphate (cyclic GMP) degradation, but was unaffected by 0.1 gM zardaverine, a type III/IV phosphodiesterase inhibitor which inhibits cyclic AMP degradation. 6 EFS (50 V, 0.2 ms, 16 Hz) induced a 3 fold increase in tissue cyclic GMP content, an action which was inhibited by L-NMMA (100;LM).7 Pyrogallol (100IM), a superoxide anion generator, also inhibited the EFS-induced relaxation by 53 ± 9%, and this effect was prevented by superoxide dismutase. 8 Chemical sympathetic denervation with 6-hydroxydopamine had no effect on the relaxant response to EFS in the endothelium-denuded PA rings.9 In endothelium-denuded branch PA rings at resting tone, L-NMMA (100 JM) significantly augmented the adrenergic contractile response, an effect which was completely reversed by L-arginine, but not by D-arginine. In the same groups of vessel rings, L-NMMA had no significant effect on the matched contractile response to exogenous noradrenaline. 10 These results suggest that NO may be released from intramural nerve endings other than adrenergic nerves (probably NANC nerves), and this leads to vasodilatation via activation of guanylyl cyclase.