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Pathogenic factors associated with chronic obstructive pulmonary disease (COPD), such as cigarette smoke, proinflammatory cytokines, and bacterial infections, can individually induce respiratory mucins in vitro and in vivo. Since co-presence of these factors is common in lungs of patients with COPD, we hypothesized that cigarette smoke can amplify mucin induction by bacterial exoproducts and proinflammatory cytokines, resulting in mucin hyperproduction. We demonstrated that cigarette smoke extract (CSE) synergistically increased gene expression and protein production of MUC5AC mucin induced by LPS or TNF-alpha in human airway epithelial NCI-H292 cells. CSE also enhanced expression and production of MUC5AC mucin induced by epidermal growth factor receptor (EGFR) ligands TGF-alpha and amphiregulin, as well as LPS- and TNF-alpha- induced expression and/or release of TGF-alpha and amphiregulin. Furthermore, (4-[(3-bromophenyl)amino]-6,7-diaminoquinazoline), a potent inhibitor of EGFR, blocked synergistic induction of MUC5AC mucin. H(2)O(2) mimicked the synergistic effects of CSE, while antioxidant N-acetyl-L-cysteine prevented synergistic induction of MUC5AC mucin by CSE. In a rat model of LPS-induced airway inflammation, concurrent cigarette smoke inhalation enhanced mucin content of the bronchoalveolar lavage fluid, muc5AC gene expression, and mucous cell metaplasia in the airways. These results suggest that cigarette smoke has the potential to synergistically amplify induction of respiratory mucins by proinflammatory stimuli relevant to COPD pathogenesis and contribute to mucin hyperproduction observed in patients with COPD.

The concentrations of dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindole-3-acetic acid (5-HIAA) in CSF obtained from the cisterna magna of 21 nonneurologically compromised dogs were determined by high-pressure liquid chromatography and electrochemical detection. A rapid method of sample preparation, which involved single filtration through a deproteinizing membrane, was used. Canine CSF obtained in this manner contained 5.78 +/- 0.78 ng of DOPAC/ml, 72.19 +/- 4.09 ng of HVA/ml, and 29.95 +/- 1.67 ng of 5-HIAA/ml. Linear regression analysis between HVA and 5-HIAA yielded a correlation coefficient of 0.4804. The neurotransmitter index, HVA/5-HIAA, was found to be more indicative of the dopaminergic metabolite HVA than the acid metabolite of serotonin, 5-HIAA (correlation coefficient with HVA = 0.5529 vs a correlation coefficient with 5-HIAA = -0.4462). A poor relationship (correlation coefficient = -0.1715) was found to exist between the 2 dopaminergic metabolites DOPAC and HVA in the CSF.

Neurotransmitter metabolites (dihydroxyphenylacetic acid [DOPAC], homovanillic acid [HVA], and 5-hydroxyindoleacetic acid [5-HIAA]) in CSF of 10 healthy dogs were evaluated with reverse-phase high-pressure liquid chromatography and electrochemical detection. Neurotransmitter metabolite concentrations determined in CSF collected from the cisterna magna were compared with those values in CSF collected from the lumbar dorsal subarachnoid space. Amounts of DOPAC (P = 0.0444), HVA (P = 0.0001), and 5-HIAA (P = 0.0316) were significantly lower in lumbar spinal fluid compared with those values in the cervical spinal fluid. Metabolite concentrations in cervical and lumbar CSF were: DOPAC = 2.81 +/- 0.73 ng/ml of CSF and 1.28 +/- 0.57 ng/ml; HVA = 98.29 +/- 12.42 ng/ml and 4.68 +/- 1.61 ng/ml; and 5-HIAA = 46.29 +/- 8.17 ng/ml and 36.96 +/- 4.07 ng/ml, respectively. Cytologic evaluations of cervical and lumbar CSF revealed a similar concentration of 3 +/- 1 WBC/microliters in both fluids. A significant (P = 0.0002) difference in protein concentration between the 2 regions was observed, with 16.1 +/- 1.8 mg of protein/dl in the cervical CSF and 27.2 +/- 2.3 mg of protein/dl in the lumbar CSF. Between the cisterna magna and lumbar dorsal subarachnoid space of dogs, a rostrocaudal gradient existed for neurotransmitter metabolites, and a caudorostral gradient existed for protein.