Thermal injury alters macrophage responses to prostaglandin E2: contribution to the enhancement of inducible nitric oxide synthase activity

Abstract

Prostaglandin E 2 (PGE 2 ) and macrophage (M) -derived reactive nitrogen intermediates (RNI) have been implicated in T cell dysfunction after thermal injury. Normally, M inducible nitric oxide synthase (iNOS) activity can be regulated by PGE 2 , however, it is unknown whether PGE 2 modulates M iNOS activity after thermal injury. Splenic M isolated from mice 7 days after thermal injury produced higher levels of RNI than M from sham mice when stimulated with lipopolysaccharide (LPS) or interferon-␥ (IFN-␥) and tumor necrosis factor ␣ (TNF-␣) in combination. PGE 2 , when added concurrently with LPS, suppressed RNI production by M from sham mice, whereas M from injured mice were unaffected. When M were pretreated with PGE 2 before LPS, RNI production was suppressed in both populations. RNI production in response to IFN-␥ or IFN-␥ and TNF-␣ in combination was enhanced by PGE 2 in both populations, however, the effect was markedly greater in M from injured mice. The PGE 2 -mediated changes in RNI production were paralleled by similar changes in iNOS protein expression, suggesting that the effect of PGE 2 was at the level of enzyme expression rather than activity. Dibutryl cAMP induced similar effects as PGE 2 , suggesting the response to PGE 2 after thermal injury is independent of potential changes in PGE 2 -induced adenylate cyclase activity and is cAMPmediated. The results indicate that M from burned mice display an altered sensitivity to PGE 2 , resulting in enhanced iNOS activity. Thus, PGE 2 , which is elevated after thermal injury and can directly suppress T cell function, may also contribute to immune dysfunction through the enhancement of M iNOS activity. J. Leukoc. Biol. 64: 740-746; 1998.

Insights into the role of γδ T lymphocytes in the immunopathogenic response to thermal injury

“…Suppression of PGE 2 production by inhibition of cyclooxygenase activity has been shown to improve immune function and survival post-burn [47]. Furthermore, PGE 2 can inhibit many aspects of macrophage function [48,49], and thermal injury also alters macrophage responses to PGE 2 [22,25]. Consistent with previous findings [24,50,51], macrophages from injured mice produced elevated amounts of PGE 2 .…”

“…Mice received a third-degree full-thickness scald burn as previously described [7,10,25]. Briefly, the mice were anesthetized by intraperitoneal injection of 65 mg/kg body weight pentobarbital sodium, and the entire dorsal surface was shaved.…”

“…Splenocyte suspensions were prepared in complete media (RPMI 1640 containing 10% heat-inactivated fetal bovine serum, 50 µM ␤-mercaptoethanol, and 5 µg/mL gentamicin, GIBCO BRL, Grand Island, NY) as described elsewhere [10,25]. Splenic macrophages were purified by adherence.…”

Injury Primes the Innate Immune System for Enhanced Toll-Like Receptor Reactivity

“…Studies performed using several animal injury models also demonstrated enhanced LPS reactivity by spleen-derived adherent cell populations and Kuppfer cells (5,15,16). Further investigations into the mechanisms associated with injury-induced perturbations in LPS responses indicated that changes in PGE 2 responses, IL-10 reactivity, and pertussis toxin-sensitive signaling pathways were involved (5,17,18). As a whole, these observations support the hypothesis that injury augments host inflammatory responses and that enhanced inflammatory reactivity may play a significant role in the development of SIRS and MODS following severe injury.…”

T Cell Suppression in Burn and Septic Injuries

“…Marano MA, 1990 andGamelli RL, 1995 documented increased systemic levels of these inflammatory mediators following burn injury altering the functional capacity of their parent cells. This elevated production of inflammatory mediators has thus been implicated for post-burn sepsis (Schwacha MG, 1998, Yang L, 1992, O'Riordain, MG, 1992. Locally released inflammatory mediators, i.e, C3a, C5a, PG, LT, O 2 -, NO, TNF , IL1, IL6, IL8, IL10, TGF act on different circulating cells (leukocytes/platelets) and other tissues (endothelium, epithelium and parenchymal cells) and neuro-endocrine axis to enhance different effector responses.…”