INFLAMMATION, CHEMOKINE EXPRESSION, AND DEATH IN MONOCROTALINE-TREATED RATS FOLLOWING FUEL-OIL FLY-ASH INHALATION

Monocrotaline-induced lung disease was used as an animal model of card iorespiratory disease to explore potential mechanisms responsible for fine particle air pollution-induced mortality in people. Saline- or mo nocrotaline-treated rats (50 mg/kg subcutaneously; day 0) were exposed by inhalation to fuel oil ash, a combustion-generated urban particula te, or filtered indoor air for 6 h on days 11-13. All animals were kil led on day 14. Measurements included bronchoalveolar lavage (BAL) cell counts and differentials, histopathology, and right ventricular systo lic pressure. Expression of the proinflammatory chemokines macrophage inflammatory protein (MIP)-2, KC, and MIP-1 alpha mRNA was determined in BAL cells by Northern analysis, and by MIP-2 immunostaining of lung and heart cells. Deaths occurred spontaneously only in monocrotaline- treated rats exposed to fly ash (42% mortality). Particle concentratio ns (mean +/- SDI throughout the exposure were 580 +/- 110 mu g/m(3) wi th a mass median aerodynamic diameter of 2.06 mu m, sigma(g) of 1.57. Neutrophils in BAL fluid were significantly elevated in monocrotaline- treated rats, and were further increased by fly ash. The total number of macrophages recovered by BAL was significantly decreased in monocro taline-treated rats exposed to either air or fly ash. Ny ash alone ind uced MIP-2 mRNA expression in BAL cells from normal animals. Both KC a nd MIP-2 mRNA were expressed in BAL cells, and MIP-2 immunostaining wa s positive in the heart and lungs of monocrotaline treated rats expose d to either air or particles. Fly ash enhanced MIP-2 immunostaining in the lung and heart of monocrotaline-treated animals. Positive, but le ss, MIP-2 immunostaining was detected in the heart and alveolar macrop hages of normal rats exposed to fly ash. MIP-2 immunostaining in the h eart was predominantly in cardiac macrophages as determined by concomi tant staining with the common leukocyte marker OX-1. Right ventricular systolic pressure was unchanged in monocrotaline-treated rats during particle exposure, indicating that deaths did not occur as a result of an acute rise in pulmonary artery pressure. These data suggest that m onocrotaline treatment and fly ash exposure result in significant infl ammation in the lung with evidence of proinflammatory signals in the h eart. Death occurred following fly ash exposure only in rats with mono crotaline-induced preexisting inflammation.