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Biomedical subjects

M C Madden

Publications and source records attributed to M C Madden.

42 records · Page 3Linked to original sources
PubMedDate not supplied

Increased expression of cyclooxygenase 2 mediates oil fly ash-induced lung injury.

We have previously shown that in vitro exposure to the combustion-derived ambient air pollutant residual oil fly ash (ROFA) induces the expression of prostaglandin H synthase 2 (COX2) in human airway epithelial cells. To determine the role of prostaglandins and COX2 expression in ROFA-induced lung injury in vivo, we have examined the effect of intratracheal ROFA instillation on COX2 expression, prostaglandin synthesis, and indices of pulmonary injury and inflammation in adult Sprague-Dawley rats. ROFA treatment induced a marked increase in the level of prostagladin E2 (PGE2) recovered in the bronchoalveolar lavage fluid (BALF), which was effectively decreased by pretreating the animals with the specific COX2 inhibitor NS398. Immunohistochemical analyses of rat airways showed concomitant expression of COX2 in the proximal airway epithelium of rats treated with ROFA. Increases in BALF protein, but not interleukin 6 (IL-6) increases or ROFA-induced polymorphonuclear neutrophils (PMN) influx into the airway, were blunted by administration of NS398 prior to ROFA instillation. These data demonstrate that prostaglandins mediate lung injury induced by exposure to ROFA and implicate increased expression of COX2 as a mechanism that contributes to the toxicity of metal-laden ambient particulate matter.

Air Pollutants↗
PubMedDate not supplied

Accumulation of iron in the rat lung after tracheal instillation of diesel particles.

Oxidant generation catalyzed by metals has been postulated to account for a lung injury following exposure to air pollution particles. In particles that are predominantly carbonaceous, it is difficult to implicate such an oxidative stress as the responsible mechanism, since concentrations of metals can be extremely low. Comparable to these air pollution particles, mineral oxide particles can include only minute amounts of metal, but lung injury following their exposure can be associated with an accumulation of endogenous iron from the host and an oxidative stress. We tested the hypothesis that diesel exhaust particulate (DEP) effects an accumulation of biologically active iron in the rat lung, with both oxidative stress and a lung injury resulting. Characterization of the DEP confirmed a high concentration of carbon, whereas metals were low in quantity. The concentration of total lavage iron in animals instilled with saline was low, but this concentration increased with exposure to DEP. Non-heme iron in lung tissue was similarly elevated after instillation of the diesel product. Particle instillation was associated with a decrease in lavage ascorbate concentration supporting an oxidative stress. Relative to saline exposure, DEP resulted in elevated lavage concentrations of the inflammatory mediators macrophage inflammatory protein-2 and tumor necrosis factor. Finally, an injury after particle instillation was evident with increased neutrophils and an elevation of lavage protein and lactic dehydrogenase. We conclude that DEP exposure effected an accumulation of iron in the rat lung. This accrual of iron was associated with an oxidative stress, release of oxidant-sensitive mediators, and a neutrophilic lung injury.

Administration, Inhalation↗
PubMedDate not supplied

The effect of ozone exposure on rat alveolar macrophage arachidonic acid metabolism.

Rat alveolar macrophages were prelabeled with 3H-arachidonic acid (3H-AA) and exposed to air or O3 (0.1-1.0 ppm) in vitro for 2 h. Alveolar macrophages released 3.6-fold more tritium at the 1.0 ppm exposure concentration compared with air-exposed macrophages. A significantly increased production of several 3H-AA metabolites, including 6-keto-PGF1 alpha, thromboxane B2, 12-hydroxy-5,8,10-heptadecatrienoic acid, prostaglandins E2 and D2, leukotrienes B4 and D4, and 15-hydroxyeicosatetraenoic acid was formed by macrophages exposed to 1.0 ppm O3 compared with air-exposed macrophages as determined by high performance liquid chromatography (HPLC) analysis. O3 exposure did not alter macrophage 3H-AA metabolism in response to calcium ionophore A23187. The largest tritiated peak observed in the HPLC chromatograms of O3-exposed cells was a polar complex of products that contained various phospholipids and neutral lipids (including diacylglycerol) and possibly degradation products of 3H-AA and some of its metabolites. These changes in macrophage arachidonic acid metabolism may play an important role in the lung response to O3 exposure in vivo.

Animals↗
PubMedDate not supplied

Characterization of a secretory phospholipase A2 in human bronchoalveolar lavage fluid.

Phospholipase A2 (PLA2) is a pivotal enzyme involved in the synthesis of the potent lipid inflammatory mediators platelet activating factor (PAF) and the eicosanoids. This study characterizes a PLA2 recovered in the bronchoalveolar lavage fluid (BALF) of healthy adult human subjects. Human BALF PLA2 exhibited characteristics of secretory PLA2s that include an activity that is acid stable, sensitive to reducing agents, and optimally requires millimolar calcium. BALF PLA2 showed marked selectivity for phosphatidylcholine containing arachidonic acid (AA) over linoleic or palmitic acids. Size exclusion chromatography showed the BALF PLA2 protein to be approximately 14 kDa in mass, consistent with it being a secretory form of PLA2. The biological significance of BALF PLA2 was tested by applying BALF concentrates to cultures of the human bronchial epithelial cell line BEAS 2B. Cultures of BEAS 2B cells treated with BALF concentrates released increased amounts of AA and produced higher levels of PAF. These data show that the lining fluid of the human respiratory tract normally contains a secretory PLA2, which may be involved in the formation of lipid inflammatory mediators in normal and pathophysiologic states in the lung.

Adolescent↗