Mechanisms of Chemically-Induced Diffuse Pulmonary Hemorrhage
Hydrocarbon oils, such as 2,6,10,14-tetramethylpentadecane (TMPD) and Hexadecane, are alkanes present in crude oil, food and in mineral oils used in cosmetics, laxatives, and food-coatings. Individuals exposed to TMPD have increased inflammatory diseases.ï¿½ To understand the pathogenesis of TMPD-induced inflammation, investigators have administered TMPD intraperitoneally (ip) to animals that develop autoantibodies, nephritis, arthritis, pneumonitis, and diffuse pulmonary hemorrhage (DPH) depending on animals’ genetic background. We established disease assessment methods, dose response, routes of exposure, and evaluated immune cells’ role in pathogenesis of TMPD-induced inflammation. Compared to none of controls, 73% of C57Bl/6 mice given TMPD (500 μl, ip) exhibited weight-loss, and pneumonitis, vasculitis and/or DPH. We established clinical (20% weight-loss), semi-quantitative, and quantitative assessments of TMPD-DPH. DPH/pneumonitis rates were much decreased at lower doses (250-125 μl, ip) of TMPD. However, oropharyngeal aspiration of as low as 6 μl TMPD caused rapid morbidity/mortality, with increased serum creatinine kinase, aspartate aminotransferase, and pneumonitis; 75% animals survived 4 μl-dose and exhibited pneumonitis/DPH. All immune cells tested were abnormal in diseased lungs at 2-weeks post-TMPD (500 μl, ip). At Day 7, prior to histopathological changes, while both Hexadecane and TMPD caused myeloid cell abnormalities, only TMPD caused lung-infiltration with B-cells that expressed B1 subset markers: CD19+CD11b+/CD19+CD5+. Such B1-cells were simultaneously reduced in their usual location (peritoneal cavity). CD19-/- mice that have less B1-cells have less DPH with ip TMPD than wildtype mice. Adoptive transfer of CD45.1+ï¿½wildtype peritoneal-fluid cells into the peritoneum of CD45.2+CD19-/- recipients led to lung-infiltration with CD45.1+ B-cells and more DPH/pneumonitis than CD19-/- recipients reconstituted with CD19-/- B-cells. Furthermore, ip TMPD induced in the lungs a differential expression of a set of immune/inflammatory genes including chemokine Cxcl13 that is known to drive B1 B- cells’ migration. However, pneumonitis/DPH development was independent of B-cells, when the lungs were directly exposed to TMPD via oropharyngeal aspiration. Thus, a systemic (ip) exposure to TMPD induces B1 B-cells to traffic from the peritoneum to the lungs and cause pneumonitis/DPH. Our observations have implications for chemically-induced inflammation, and DPH that is often a fatal complication in humans with inflammatory diseases and upon exposure to pesticides/cocaine.