To investigate the function of prostaglandin H synthase-1 and synthase-2 (PGHS-1 and PGHS-2) in the normal lung and in allergic lung responses, we examined allergen-induced pulmonary inflammation and airway hyperresponsiveness in wild-type mice and in PGHS-1 -/-and PGHS-2 -/-mice. Among nonimmunized saline-exposed groups, we found no significant differences in lung function or histopathology, although PGE 2 was dramatically reduced in bronchoalveolar lavage (BAL) fluid from PGHS-1 -/-mice, relative to wild-type or PGHS-2 -/-mice. After ovalbumin sensitization and challenge, lung inflammatory indices (BAL cells, proteins, IgE, lung histopathology) were significantly greater in PGHS-1 -/-mice compared with PGHS-2 -/-mice, and both were far greater than in wild-type mice, as illustrated by the ratio of eosinophils in BAL fluid (8:5:1, respectively). Both allergic PGHS-1 -/-and PGHS-2 -/-mice exhibited decreased baseline respiratory system compliance, whereas only allergic PGHS-1 -/-mice showed increased baseline resistance and responsiveness to methacholine. Ovalbumin exposure caused a modest increase in lung PGHS-2 protein and a corresponding increase in BAL fluid PGE 2 in wild-type mice. We conclude that (a) PGHS-1 is the predominant enzyme that biosynthesizes PGE 2 in the normal mouse lung; (b) PGHS-1 and PGHS-2 products limit allergic lung inflammation and IgE secretion and promote normal lung function; and (c) airway inflammation can be dissociated from the development of airway hyperresponsiveness in PGHS-2 -/-mice.
Particulate matter (PM) air pollution may increase symptom severity in allergic asthmatics. To examine possible interaction, or greater than additive responses, between PM effects and allergic responses, an ovalbumin-sensitized and challenged (OVA) mouse model of allergic airways disease was utilized. After challenge, mice were intratracheally instilled with saline vehicle or 3 mg/kg (approximately 60 microg) residual oil fly ash (ROFA), a transition metal-rich emission source PM sample. Physiological and inflammatory responses were examined 1, 3, 8, and 15 d later. In response to intravenously administered methacholine, ROFA increased total respiratory system resistance and decreased compliance 1 d after exposure, whereas effects of OVA lasted at least 15 d after exposure. Significant interactions between OVA and ROFA were mainly observed 8 d after challenge and exposure, especially with respect to compliance. A strong interaction (p < 0.01) between OVA and ROFA exposure resulted in 8-fold (1 d) and 3-fold (3 d) increases in bronchoalveolar lavage (BAL) fluid eosinophil numbers. A similarly strong interaction (8-fold) was observed in BAL fluid interleukin-4 (IL-4) 1 d after challenge and exposure. Significant though less strong interactions were also found with respect to IL-4 and IL-5 by 3 d postchallenge/exposure. This study shows that allergen challenge and exposure to emission source particulate matter containing relatively high levels of transitions metals can interact to increase Th2 cytokine production, eosinophil recruitment, and airway hyperresponsiveness in previously sensitized mice.
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