Localized vs. systemic inflammation in guinea pigs: a role for prostaglandins at distinct points of the fever induction pathways?

Abstract

In guinea pigs, dose-dependent febrile responses were induced by injection of a high (100 g/kg) or a low (10 g/kg) dose of bacterial lipopolysaccharide (LPS) into artificial subcutaneously implanted Teflon chambers. Both LPS doses further induced a pronounced formation of prostaglandin E 2 (PGE2) at the site of localized subcutaneous inflammation. Administration of diclofenac, a nonselective cyclooxygenase (COX) inhibitor, at different doses (5, 50, 500, or 5,000 g/kg) attenuated or abrogated LPS-induced fever and inhibited LPS-induced local PGE2 formation (5 or 500 g/kg diclofenac). Even the lowest dose of diclofenac (5 g/kg) attenuated fever in response to 10 g/kg LPS, but only when administered directly into the subcutaneous chamber, and not into the site contralateral to the chamber. This observation indicated that a localized formation of PGE 2 at the site of inflammation mediated a portion of the febrile response, which was induced by injection of 10 g/kg LPS into the subcutaneous chamber. Further support for this hypothesis derived from the observation that we failed to detect elevated amounts of COX-2 mRNA in the brain of guinea pigs injected subcutaneously with 10 g/kg LPS, whereas subcutaneous injections of 100 g/kg LPS, as well as systemic injections of LPS (intra-arterial or intraperitoneal routes), readily caused expression of the COX-2 gene in the guinea pig brain, as demonstrated by in situ hybridization. Therefore, fever in response to subcutaneous injection of 10 g/kg LPS may, in part, have been evoked by a neural, rather than a humoral, pathway from the local site of inflammation to the brain. lipopolysaccharide; febrile response; prostaglandin E 2; cyclooxygenase-2; immune system-to-brain communication MOST EXPERIMENTAL STUDIES employing bacterial lipopolysaccharide (LPS) to induce fever use a systemic route of administration, such as intraperitoneal, intravenous, or intra-arterial injections of the pyrogen. These treatments result in a generalized systemic inflammatory response, which is accompanied by increased measurable amounts of proinflammatory cytokines and LPS in the circulation (10,14,17,28,32). To study a cytokine release within a local area of inflammation, experimental models have been introduced in which LPS is administered locally, rather than systemically, into a subcutaneous air pouch in rats (8,22,23) or a subcutaneously implanted artificial Teflon chamber in guinea pigs (29,30,34). LPS that is injected into the air pouch (8) or the subcutaneous chamber (29) is not measurable in the systemic circulation 1 h after its injection. This observation does, however, not exclude the possibility that a small fraction of the injected LPS might have leaked from the air pouch or the chamber immediately after the injection procedure. Among the pyrogenic cytokines (TNF, IL-1, or IL-6) that are produced within the site of localized subcutaneous inflammation, IL-6 is the only putative endogenous pyrogen that enters the circulation in significant quantities. It has therefore been proposed that...

Endothelial-Specific Knockdown of Interleukin-1 (IL-1) Type 1 Receptor Differentially Alters CNS Responses to IL-1 Depending on Its Route of Administration

“…Recent studies showed that, along the potential neural pathways of neuroimmune communication, nonendothelial IL-1R1 and Cox-2 may play important roles. Thus, Rummel et al (2005) showed that the production of prostaglandin E 2 at the site of local inflammation is critical for the induction of fever, and Samad et al (2001) showed spinal neuronal expression of Cox-2 and IL-1R1 relay signals from localized peripheral inflammation to the brain via ascending sensory nerve tracts. Therefore, CNS activation via these neural pathways would still depend on the expression of Cox-2 and IL-1R1, although endothelial expression of IL-1R1 and Cox-2 may not be involved.…”

Fever, fever patterns and diseases called ‘fever’ – A review

“…It has been suggested that localised formation of PGE2 at sites of inflammation contribute to fever generation by activating cold-sensitive cutaneous nerves, which, in turn, transmit fever signals to parts of the brain responsible for fever generation [28]. The transmission of fever signals via the vagus nerve follows a more complex pathway.…”

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

“…Better models have been developed of so-called restricted local inflammation that do not induce brain COX-2 and have low to undetectable circulating cytokines. In these studies the fever response could be attenuated by very low doses of locally administrated diclofenac (Rummel et al, 2005) and could be shown to be dependent on the presence of TLR4, IL-1R1, IL-6 and COX-2 (Zhang et al, 2008).…”

“…While largely neglected at that time this study gained more attention when the antipyretic effect of local anesthetics blocking C-fiber-signaling was verified by Roth's group (Ross et al, 2000;Roth and De Souza, 2001). Several models for local inflammation have been used, including subcutaneous turpentine (Cooper and Rothwell, 1991;Fantuzzi et al, 1997;Horai et al, 1998;Kozak et al, 1998;Laflamme and Rivest, 1999;Leon et al, 1996), carrageenaninduced paw edema (Guay et al, 2004;Ibuki et al, 2003;Oka et al, 2007;Posadas et al, 2004;Prajapati et al, 2014), or immune stimuli administrated in artificial subcutaneous chambers (Cartmell et al, 2000;Miller et al, 1997;Rummel et al, 2005;Rummel et al, 2011;Zhang et al, 2008). However, most studies used local inflammation-models primarily to demonstrate an endotoxin-free cytokine-induced sickness syndrome (Horai et al, 1998;Kozak et al, 1998;Leon et al, 1996;Miller et al, 1997;Rivest et al, 2000) and not to investigate the role played by the afferent neurons.…”