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 cardiorespiratory disease to explore potential mechanisms responsible for fine particle air pollution-induced mortality in people. Saline- or monocrotaline-treated rats (50 mg/kg subcutaneously; day 0) were exposed by inhalation to fuel oil ash, a combustion-generated urban particulate, or filtered indoor air for 6 h on days 11-13. All animals were killed on day 14. Measurements included bronchoalveolar lavage (BAL) cell counts and differentials, histopathology, and right ventricular systolic 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 concentrations (mean +/- SDI throughout the exposure were 580 +/- 110 mu g/m(3) with 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 monocrotaline-treated rats exposed to either air or fly ash. Ny ash alone induced MIP-2 mRNA expression in BAL cells from normal animals. Both KC and MIP-2 mRNA were expressed in BAL cells, and MIP-2 immunostaining was positive in the heart and lungs of monocrotaline treated rats exposed to either air or particles. Fly ash enhanced MIP-2 immunostaining in the lung and heart of monocrotaline-treated animals. Positive, but less, MIP-2 immunostaining was detected in the heart and alveolar macrophages of normal rats exposed to fly ash. MIP-2 immunostaining in the heart was predominantly in cardiac macrophages as determined by concomitant 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 monocrotaline treatment and fly ash exposure result in significant inflammation in the lung with evidence of proinflammatory signals in the heart. Death occurred following fly ash exposure only in rats with monocrotaline-induced preexisting inflammation.