Enhanced Release of Prostaglandin E₂ from Macrophages of Rats with Silicosis

Abstract

The pathogenesis of silicosis results, in part, from interactions between silica particles and alveolar macrophages (AM) with release of cytokines and other mediators. Different arachidonic acid metabolites have been shown to promote or to suppress inflammation and fibrosis. We designed experiments to study the production of cyclooxygenase metabolites and tumor necrosis factor-alpha (TNF-alpha) from macrophages during active silicosis. Macrophages were harvested from rats 5 to 7 mo after an 8-day silica aerosol exposure. Upon in vitro culture of AM, the spontaneous release of prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and prostaglandin D2 (PGD2) of silica-exposed animals was higher than that of sham-exposed animals. Moreover, AM from silicotic rats displayed an increased sensitivity to low concentrations of lipopolysaccharide (LPS, 10 ng/ml) and released copious amounts of PGE2 and TXB2. When compared with similarly enhanced release of TNF-alpha from AM of silica-exposed rats, PGE2 production occurred later and started to increase when TNF-alpha production declined. Addition of the cyclooxygenase blocker indomethacin augmented TNF-alpha production, whereas the addition of PGE2 counteracted TNF-alpha release. Also peritoneal macrophages, which did not have direct contact with silica particles, released enhanced levels of PGE2 in response to low LPS doses. We conclude that AM and other macrophages from silica-exposed rats are preactivated and display an enhanced prostanoid production that could serve anti-inflammatory or immunomodulating roles in silicosis.

Agglomerates of ultrafine particles of elemental carbon and TiO2 induce generation of lipid mediators in alveolar macrophages.

“…Mohr et al (10) reported that AMs of rats exposed to silica with a recovery period of several months showed an increased level of PGE 2 and TXB 2 that occurred after the elevated TNF-α release declined. These authors concluded that AMs of silica-exposed rats display an enhanced PGE 2 production that could serve anti-inflammatory and immunomodulating roles in silicosis.…”

“…Lipid mediators may play a major role in promoting or eliciting responses of lung tissue to air pollutants such as ozone (6,7), sulfurrelated species, especially sulfite (8,9), silica (10,11), and residual oil fly ash (12). Among the lipid mediators, platelet-activating factor and products of the 5-lipoxygenase (5-LO) pathway such as leukotriene B 4 (LTB 4 ) are known to stimulate immune cells such as polymorphonuclear neutrophil (PMNs) (13)(14)(15).…”

Modulation by nitric oxide of prostaglandin biosynthesis in the rat

“…Furthermore, PGE2 and PGI2 have been found to inhibit the release of TNF-a from activated mouse peritoneal macrophages (Marcinkiewicz, 1991), rat alveolar macrophages (Mohr et al, 1992) and human peripheral blood mononuclear cells (Haynes et al, 1992). Since it is known that this cytokine induces iNOS, these findings support the hypothesis that the NO-mediated overproduction of prostaglandins may also act as a negative feedback preventing excessive or prolonged induction of iNOS (Figure 7).…”

Synergistic induction of cyclooxygenase-II by bacterial lipopolysaccharide in combination with particles of medical device materials in a murine macrophage cell line J774A.1

“…Mohr at al. 25 observed an enhancement of COX activity in the alveolar macrophages of silica-exposed rats, and Hukkanen et al 26 showed that prosthesis wear particles phagocytosed by macrophages found in the interface membrane of loosened total hip replacements are likely to contribute to the induction of COX-II by human macrophages.…”