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Department of Experimental Pathology, William Harvey Research Institute, St. Bartholomew’s & The Royal London School of Medicine and Dentistry, London EC1M 6BQ; and
* Department of Biochemical Pharmacology, William Harvey Research Institute, St. Bartholomew’s & The Royal London School of Medicine and Dentistry, London EC1M 6BQ
1Correspondence: E-mail: d.w.gilroy{at}qmul.ac.uk
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: resolution • cyclooxygenase • lipoxygenase • arachidonic acid • eicosanoids
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. These checkpoints are managed by endogenous mediators that act as either stop or go signals, with some mediators that drive inflammation paradoxically, acting as suppressers of the response. One example of this are the eicosanoids, in particular, cyclooxygenase (COX) and lipoxygenase metabolites of arachidonic acid (AA), a fatty acid released from membrane phospholipids by the actions of phospholipase A2 (PLA2). There are three broad classes of phospholipases based on cellular disposition and calcium dependence, and include calcium-independent PLA2 (iPLA2), secretory PLA2 (sPLA2) and cytosolic PLA2 (cPLA2) (2)
. Each class of phospholipase A2 is further subdivided into isoenzymes for which there are 10 for mammalian sPLA2, at least 3 for cPLA2, and 2 for iPLA2. Classically, COX-derived prostaglandins (PGs) and lipoxygenase-derived leukotrienes (LTs) are early release mediators that, either alone or in synergy with other mediators, initiate exudate formation and inflammatory cell influx (3)
. However, its becoming more apparent that certain classes of eicosanoids are also important for inflammatory resolution by virtue of their ability to stop inflammatory cell influx and facilitate cell clearance (4
, 5)
(6)
. For instance, in an established murine air pouch model injected with TNF
, there is an immediate influx of PMNs concomitant with PGE2 and LTB4 production at the onset, but a switch to LT-derived lipoxin A4 (LxA4) synthesis during resolution, which stops cell trafficking (5)
and contributes to inflammatory cell clearance by enhancing phagocytosis of effete cells (7)
. Similarly, in a carrageenin-induced pleurisy we have shown that the onset phase of the response is characterized by rapid PMN influx mediated in part by PGE2 synthesis. As inflammation progresses into resolution PGE2 synthesis declines, giving way to a predominance of COX 2-derived PGD2 and its cyclopentenone PG breakdown product, 15deoxy
12-14PGJ2, both of which play an important role in mediating resolution (4)
. Therefore, it would appear that in acute pleurisy there are two waves of AA release: one at onset for the synthesis of proinflammatory PGE2 and a second at resolution for the synthesis of anti-inflammatory PGD2 and cyclopentenone PGs. We earlier identified the COX enzymes involved in both phases of AA metabolism in the rat pleurisy model (4)
; here, we set out to determine the PLA2 isoforms responsible for the phenomenon of eicosanoid class switching in acute resolving inflammation. Indeed, the exact role each PLA2 plays in initiating, maintaining, and subsequently resolving inflammation is unknown. We found that type VI iPLA2 was the principal isoform expressed at the onset of the lesion; it initiated cell trafficking through the release of a range of typically proinflammatory lipid mediators and, surprisingly, IL-1ß. During resolution, however, there was an induction of sPLA2 (types IIa and V), which through the synthesis of LxA4 and platelet-activating factor (PAF), brought about the subsequent up-regulation of type IV cPLA2, which released AA for synthesis by COX 2 to generate anti-inflammatory PGs. |
MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. For collection of pleural exudates at designated times, pleural cavities were lavaged with 1 mL of 3.15% (w/v) sodium citrate in physiological saline. Weighing the collected inflammatory exudates assessed edema formation; cells were counted with a Coulter® counter (model DN; Coulter Electronics, Luton, UK). All animal experiments were done in accordance with the UK Home Office regulations for the care and use of animals.
Drug administration
The iPLA2 inhibitor Haloenol lactone (HELSS) (8)
was dosed at 3.0, 10, and 30 nmol, the cPLA2 inhibitor, arachidonyltrifluoromethyl ketone (AACOCF3) (9)
, at 3.0, 10, and 30 nmol; the sPLA2 inhibitor oleyloxyethyl phosphorylcholine (OOPC) (10)
was used at 30, 90, and 270 nmol. To examine the effects of these inhibitors on the early phase of acute pleurisy, all drugs were administered into the pleural cavity concomitant with carrageenin and their effects assessed 3 h later. To assess the role of sPLA2 during resolution, OOPC was injected locally into the pleural cavity 24 h after carrageenin injection and its effects on resolution were determined at 48 h. Likewise, to discern the role of cPLA2 at the later phase of resolution, AACOCF3 was injected into the pleural cavity 48 h after carrageenin injection and its effects on resolution were determined at 72 h.
Western blot
Cell monolayers were dispersed with 0.05% trypsin in PBS, 10 mM EDTA and cell pellets were snap-frozen in 3 mL of PBS containing 10 mM EDTA, 1 mg mL-1 soybean trypsin inhibitor, 0.01% leupeptin, 1 mM phenyl-methane-sulfonyl fluoride, and 1 mM sodium orthovanadate. Once thawed, cell lysates were clarified by centrifugation at 13,000 x g for 5 min. Protein concentrations were measured by Bradford assay and identical concentrations were incubated with 250 µL sample buffer for 5 min at 90°C before SDS-PAGE analysis by Western blot and detection by DAB. To determine extracellular sPLA2 protein expression, cell-free inflammatory exudates of equal protein concentrations were analyzed by Western blot. Antibodies for COX 1, COX 2, type IV cPLA2, type VI iPLA2, and types IIa and V sPLA2 were from Santa Cruz (Santa Cruz, CA, USA) and Cayman Chemicals (Ann Arbor, MI, USA).
Corticosterone measurements
Corticosterone was measured by radioimmunoassay (ICN Biomedical, Costa Mesa, CA, USA) in the peripheral blood and pleural exudates of rats bearing a carrageenin-induced pleurisy. To obtain baseline levels, corticosterone was measured in the peripheral blood and pleural washouts of rats injected intrapleurally with saline. In our experience circulating corticosterone levels begin to rise substantially after 5 min in response to stress and trauma. To get a true picture of the effects of a local inflammation on circulating and localized corticosterone levels, all animals were killed within 3 min of removal from animal holding rooms.
sPLA2 activity assay, eicosanoid, and cytokine measurements
Extracellular sPLA2 activity was determined by an sPLA2 enzyme assay kit from Cayman Chemicals. This kit does not distinguish between sPLA2 subtypes. PGE2, PGD2, and LTB4 were measured by EIA whereas PAF was measured by RIA (Amersham Pharmacia Biotech, Amersham, UK). LxA4 was quantified by ELISA (Neogen, Lansing, MI, USA) and IL-1ß was determined by commercial ELISA kits (R&D Systems, Oxon, UK). All measurements were made in cell-free inflammatory exudates.
In vitro cell culturing and treatment of cells
A549 cells were cultured in Dulbecco’s modified Eagle medium (DMEM)/F-12 containing 10% fetal calf serum. These cells were deprived of serum for 24 h, then incubated with IL-1ß (1 ng/mL) and/or PAF (10 ng/mL) for 6 h. RAWs and fibroblasts were maintained in DMEM containing 10% fetal calf serum and treated with LxA4 (1 ng/mL) in the presence and absence of serum for 6 and 24 h but without prior serum starvation. All cells (European Collection of Cell Cultures, Salisbury, Wiltshire, UK) were maintained in an atmosphere of 5% CO2 at 37°C and used experimentally at a confluence of 60–70%.
Statistics
Statistical analysis was performed using an ANOVA, followed by a Bonferroni-T test. Data are expressed as mean ± SE of the mean.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A). Analysis of cell-free inflammatory exudates by Western blot showed that levels of extracellular sPLA2 (types IIa and V) protein increased progressively, reaching a maximum at 72 h (Fig. 1B
). This gradual increase in extracellular sPLA2 protein expression was reflected by an increase in cell-free inflammatory exudate total sPLA2 enzyme activity (Fig. 1C
). Type VI iPLA2 protein expression, on the other hand, was restricted to the early phase of the acute reaction being detectable up to 24 h only (Fig. 1D
). In contrast, type IV cPLA2 was barely detectable during the early phase of this acute lesion but was found to increase progressively during resolution, peaking in expression at 72 h (Fig. 1E
). This increase in type IV cPLA2 was mirrored by a parallel increase in COX 2 expression (Fig. 1F
). In all samples analyzed cPLA2 and COX 2 were found to increase in tandem, suggesting there may be a functional interaction or enzymic coupling between these two proteins for the synthesis of anti-inflammatory PGD2 and cyclopentenone PGs during inflammatory resolution as previously published (4)
. In summary, type VI iPLA2 was highly expressed at the onset phase of the pleurisy whereas type IIa and V sPLA2 and type IV cPLA2 were the predominant isoforms expressed during resolution.
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Corticosterone levels throughout the time course of an acute pleurisy
Until now it has been widely assumed that the predominant PLA2 isoforms that drive the inflammatory response through release of AA for eicosanoid synthesis are sPLA2 and cPLA2, with iPLA2 playing more of a role in membrane remodeling (11)
. Therefore, it was surprising to find type VI iPLA2 highly expressed at the onset in carrageenin-induced pleurisy. We sought to understand how PLA2 isoform expression may be regulated during acute resolving inflammation. Glucocorticoids are potent regulators of the inflammatory response and of PLA2 in particular (12)
. For this reason, we measured endogenous corticosterone in the peripheral blood and local inflammatory exudates of rats bearing an acute pleurisy vs. rats injected intrapleurally with saline. Not surprisingly, peripheral blood and pleural exudate levels of corticosterone were both highest at onset but declined to near baseline levels at 24 h, being virtually undetectable during resolution (Fig. 2
A). By contrast, in peripheral blood of animals injected with saline into the pleural cavity, there was a modest spike in levels of corticosterone that probably resulted from the stress of introducing a blunted needle through the intercostal muscle and into the pleural cavity. As glucocorticoids suppress both cPLA2 (13)
and sPLA2 expression (14)
, we hypothesized that the low level of these isoforms at onset results from the suppressive effects of corticosterone present in the inflammatory exudate at this time and that the rapid decline in glucocorticoids allowed for their elevation during resolution. This reasoning would mean that type VI iPLA2 expression is refractory to the suppressive effects of glucocorticoids. To test this hypothesis, we examined the effects of dexamethasone on cPLA2 and iPLA2 protein expression in cultured A549 cells, a cell line well characterized by us for PLA2 expression (15)
. IL-1ß more than doubled type IV cPLA2 expression, with dexamethasone reversing these stimulated levels by 
40% (Fig. 2B
). In contrast, IL-1ß had no significant effect on type VI iPLA2 (Fig. 2B
), causing only a modest 7% increase in expression over and above controls. Dexamethasone as well had little effect on IL-1ß-treated type VI iPLA2 causing a <10% reduction in expression. Thus, the temporal profile of phospholipase isoform expression throughout an acute pleurisy may be controlled by endogenous corticosterone.
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Role of PLA2 isoform during the onset phase of acute inflammation
To determine the functional contribution of PLA2 isoforms to carrageenin-induced pleurisy, a pharmacological approach was taken using specific iPLA2, cPLA2, and sPLA2 inhibitors. These drugs were administered locally not only to bypass potential effects on systemic leukocyte-endothelial interaction but to determine the contribution of local inflammatory cells to the development and termination of an acute inflammation. HELSS is a potent and irreversible inhibitor of iPLA2 (8)
, possessing a 1000-fold selectivity for iPLA2 over cPLA2 and sPLA2 and, when administered into the pleural cavity concomitant with carrageenin, brought about a concentration-dependent and significant reduction in inflammatory cell numbers (Fig. 3
A), but did not alter exudate formation (data not included). This inhibition of iPLA2 resulted in the local reduction of PGE2, LTB4, IL-1ß, and PAF (Fig. 3B-E
, respectively). The sPLA2 inhibitor OOPC (10)
, was administered at the same concentration as HELSS but had no effect on inflammation, prompting us to use higher levels; 270 nmol began to exert a significant reduction in inflammatory cell influx (Fig. 3A
) possibly through the inhibition of IL-1ß (Fig. 3F
). This very high level of OOPC required to alter inflammation and that does not distinguish between subtypes of sPLA2 may reflect the relatively minor role sPLA2 subtypes play in driving the onset phase of acute inflammation. The cPLA2 inhibitor AACOCF3 (9)
had no effect on inflammatory cell numbers, exudate formation, or any of the proinflammatory mediators measured at this time (data not included). These experiments suggest that of the PLA2 family of enzymes, type VI iPLA2 plays an important role in driving acute inflammation.
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Dissecting the role of cPLA2 during acute inflammatory resolution
From previous studies we found that COX 2 protein expression was maximal during the resolving phase of an acute pleurisy and brought about resolution through the release of PGD2 and 15deoxy12-14 PGJ2 (4)
. In this study, COX 2 expression increased in tandem with type IV cPLA2, suggesting that this calcium-dependent PLA2 isoform may be responsible for releasing AA for the generation of COX 2-derived anti-inflammatory PGD2 and 15deoxy12-14 PGJ2. To test this hypothesis, we administered the selective cPLA2 inhibitor AACOCF3 locally into the pleural cavity 48 h before the peak of cPLA2 expression and assessed resolution at 72 h. iPLA2 and sPLA2 inhibitors were also administered locally at this time. AACOCF3 dose-dependently increased inflammatory cell numbers and exudate formation (Fig. 4
A, B), reaching significance at the highest dose. Consequently, PGD2 in the inflammatory exudate was significantly inhibited (Fig. 4C
), suggesting that the release of AA for the synthesis of COX 2-derived PGD2 during inflammatory resolution is facilitated by type IV cPLA2. As no other phospholipase isoform was expressed in this time frame, it was not surprising to find that neither the iPLA2 nor the sPLA2 inhibitor affected resolution. Injection of AACOCF3 alone into the pleural cavity of naïve rats did not elicit an inflammatory response, confirming that the proinflammatory effects of this drug were not due to direct irritation of the pleural cavity.
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The role of sPLA2 during acute inflammatory resolution
Type IIa and V sPLA2 were maximally expressed within inflammatory cells during resolution at 24–48 h, suggesting a possible role in switching off inflammation. To test this we administered the sPLA2 inhibitor OOPC at 24 h and found it prevented resolution by significantly increasing cell numbers at 48 h (Fig. 5
A), but had no effect on exudate formation. Selective cPLA2 and iPLA2 inhibitors did not alter resolution at this time; as with AACOCF3, OOPC did not have an irritant effect on the naïve pleural cavity (data not included). Given that we consistently found the sequential expression of sPLA2, followed by cPLA2/COX 2, we questioned whether expression of cPLA2/COX 2 is dependent on intracellular sPLA2 enzyme activity. After inhibiting sPLA2 there was a distinct reduction in COX 2 and type IV cPLA2 (Fig. 5B
) protein expression at 72 h, suggesting that types IIa and/or V sPLA2 release a mediator (or mediators) that contributes to the subsequent up-regulation of type IV cPLA2 and COX 2. In an attempt to identify such putative mediators, we found that PAF and LxA4 (Fig. 5C
) were increased coincident with types IIa and V sPLA2 and that levels of both of these lipid mediators were suppressed in the inflammatory exudates of animals dosed with OOPC (Fig. 5D
).
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PAF and LxA4 elevate cPLA2 and COX 2 in isolated cells
Inhibition of types IIa and V sPLA2 resulted in a decrease in PAF and LxA4 and a subsequent reduction in cPLA2 and COX 2, suggesting that sPLA2-derived PAF and LxA4 may be collectively responsible for the induction of COX 2 and type IV cPLA2. We tested this hypothesis in vitro and found that in A549 cells PAF synergized with IL-1ß to bring about a 25% increase in type IV cPLA2 expression but was without effect on COX 2 (Fig. 6
A). In contrast, LxA4 increased COX 2 protein expression in RAW 264.7 macrophages (Fig. 6B
) and human primary dermal fibroblasts (Fig. 6C
). In macrophages and fibroblasts, LxA4 was most effective at increasing COX 2 expression at the early time point of 6 h in the absence of serum whereas at 24 h, LxA4 exerted its greatest effect on COX 2 induction in the presence of serum. Thus, it appears that during the resolution of acute pleural inflammation, types IIa and V sPLA2 play an important role in the subsequent induction of anti-inflammatory type IV cPLA2 and COX 2, possibly through the combined actions of (at least) PAF and LxA4.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, IL-1ß, and IL-6 and is critical in limiting the severity of inflammatory reactions (16)
. In a carrageenin-induced pleurisy there is a characteristic peak in circulating and local endogenous corticosterone levels during onset that is undetectable during the latter resolving phase. It is well known that the synthetic glucocorticoid dexamethasone inhibits both cPLA2 and sPLA2 expression in vitro (13
, 14)
. Regulation of iPLA2 by glucocorticoids, however, is less well understood. For this reason, we treated IL-1ß-stimulated A549 cells with dexamethasone and found that cPLA2 expression was inhibited whereas iPLA2 was unaffected, suggesting that this calcium-independent isoform is refractory to the inhibitory effects of glucocorticoids. We, therefore, propose that the high local levels of endogenous corticosterone at onset, which decline during resolution, are responsible for the differential expression of PLA2 isoforms during the course of an acute resolving pleurisy.
The finding that iPLA2 is the principal phospholipase isoform that contributes significantly to the influx of PMNs through the synthesis of proinflammatory lipid mediators and cytokines is surprising, as it is generally held that iPLA2 is involved in membrane phospholipid composition and remodeling (17
, 18)
. However, in human peripheral blood monocytes incubated with either 12-O-tetradecanoate phorbol-13 acetate or opsonized zymosan, iPLA2 has been shown to release AA for the synthesis of a range of COX metabolites (19)
whereas in arginine vasopressin-stimulated A10 smooth muscle cells, AA was released in a manner that was calcium independent and sensitive to the selective iPLA2 inhibitor, bromoenol lactone (20)
. In pancreatic islet cells, AA hydrolysis from membrane phospholipids induced by A23187, thapsigargin, or the intracellular calcium chelator BAPTA is prevented by bromoenol lactone (21)
. Therefore, it appears that iPLA2 possesses the ability to generate fatty acid metabolites; we speculate that under circumstances when cPLA2 and sPLA2 expression is suppressed, iPLA2 becomes the principal AA hydrolyzing phospholipase. However, besides releasing fatty acid precursors for the generation of bioactive eicosanoids, iPLA2 has other roles in inflammation. For instance, it is critical for IgG-mediated phagocytosis in human monocytes (22)
as well as proinflammatory cytokine processing (23)
. Regarding the latter, it was observed that depletion of intracellular potassium levels results in the activation of iPLA2 which in turn contributes to the conversion of inactive proIL-1ß by IL-converting enzyme (caspase 1) to active IL-1ß. These authors also found that pro-IL-1ß processing was suppressed by an increase in cPLA2. Thus, low levels of type IV cPLA2 in the background of high type VI iPLA2 expression at the onset phase of the rat pleurisy may represent an endogenous regulatory system favoring the maturation of active IL-1ß to help drive the inflammatory response. From the work of others and that presented here, it seems that iPLA2 has many diverse roles during inflammation and tissue injury, including eicosanoid biosynthesis, cytokine processing, and clearance of inflammatory cells. The precise role it plays probably depends on the site of injury and the nature of the injurious stimulus.
In carrageenin-induced pleurisy, sPLA2 protein expression (types IIa and V) peaked at 36 and 48 h. The importance of sPLA2 at this time was for synthesis of LxA4 and PAF. Lipoxins are a family of naturally occurring lipid mediators that possess potent suppressive effects on leukocyte function (24)
and are formed concurrently with spontaneous resolution in clinical and experimental settings, where they switch off inflammatory cell infiltration (5)
and enhance macrophage phagocytosis of apoptotic cells (7)
. Likewise, PAF has been shown to enhance macrophage phagocytosis of red blood cells (25)
and latex beads (26)
. At 48 h in rat pleurisy, there is intense phagocytosis of PMNs as evidenced by the appearance of Reiter cells (macrophages that phagocytosed effete PMNs), representing 2–3% of the total cell population. Because it is at about this time that LxA4 and PAF levels are maximal, the relevance of LxA4 and PAF during resolution could be to enhance macrophage phagocytosis of effete PMNs, paving the way for complete resolution. In addition to a putative role in cell clearance, it was found that LxA4 and PAF up-regulated COX 2 and cPLA2. We have shown that COX 2 plays a role in bringing about resolution in this model through the synthesis of PGD2 and its cyclopentenone PG metabolite 15deoxy12-14 PGJ2 (4)
. In this report we show that the PLA2 isoform required to release AA for metabolism by COX 2 is type IV cPLA2. In fact, in all samples analyzed by Western blot, we observed a tandem expression of cPLA2 with COX 2, supporting the emerging concept that there is the need for an association or functional coupling of AA-releasing phospholipases with COX enzymes for the generation of PGs (27
28
29
30
31)
. In COS-1 cells, for example, COX 1 and COX 2 couple specifically to cPLA2, but not sPLA2, for PGE2 production (30)
whereas in mast cells interaction between sPLA2 and COX 1 is required for the immediate release of PGD2 whereas delayed PGD2 synthesis is facilitated by cPLA2 coupling to COX 2 (27)
. Thus, the differential association of PLA2s with COX enzymes probably depends on the cell systems and stimuli used. In the rat carrageenin pleurisy, at least, it appears that cPLA2 couples preferentially with COX 2 during resolution for the generation of anti-inflammatory prostaglandins.
Additional evidence for a role for sPLA2 in the resolution of acute inflammation comes from observations between different strains of mice. In an attempt to discern a role for sPLA2 in inflammation by generating mice defective in the gene, it was shown that the sPLA2 gene in several mouse strains, including C57BL/6, contains a natural mutation resulting in an inactive gene product, whereas strains such as BALB/c and DBA/1 have normal sPLA2 genotype (32)
. In the present report, we compared the inflammatory response in several strains of mice and it became apparent during resolution in a carrageenin-induced air pouch that total inflammatory cell numbers were significantly greater (P
0.05) in sPLA2 disrupted C57BL/6 mice (50±3.5x106) than in normal BALB/c animals (27±3.7x106). The level of inflammation was virtually the same during the early onset phase in both strains. This suggests that sPLA2 has a minor role in driving a model of acute resolving inflammation but a significant role in switching it off. It is appreciated that comparing inflammatory parameters between different strains of mice is not strictly correct, as many theoretical differences can contribute to dissimilar inflammatory responses; nevertheless, it is an interesting comparison that is consistent with our studies using pharmacological intervention in rat pleurisy.
Some studies have been carried out on cPLA2 null mice to discern the role of this isoform in the liberation of AA and the generation of eicosanoids. In a model of acute lung injury induced by septic shock or acid aspiration, it was shown that levels of TxB2, LTB4, and the peptido-leukotrienes in bronchoalveolar lavage fluid were significantly reduced in comparison to wild-type animals, implicating a role for cPLA2 in eicosanoid generation in lung inflammation (33)
. However, in a model of hypoxic pulmonary vasoconstriction, there was no significant reduction in left lung tissue homogenates levels of PGE2, TxB2, or PGF2 between wild-type and knock out animals (34)
. There is no apparent reason for these contrasting results except that in hypoxic lung injury, there is an absence of an inflammatory cell influx, which is a predominant component of irritant-induced lung injury. Thus, the role of phospholipase isoforms in inflammation may be critically dependent on the etiology of the disease process being examined. We propose that the importance of the findings in this paper may be of great relevance to the treatment of rheumatoid arthritis. Rheumatoid arthritis is characterized by flares in joint swelling, followed by remission, with ongoing pannus tissue formation gradually eroding away articular cartilage and bringing about joint destruction. These flare and remission events are akin to onset and resolution in acute experimental inflammation inasmuch as the cell profile and mediators that initiate the response are similar. In treatment of rheumatoid arthritis, nonsteroidal anti-inflammatory drugs (COX inhibitors) are prescribed for several months or even years, yet show little evidence of decreasing disease progression or joint destruction (35)
. Given the role for COX 2 in switching off acute inflammation, we previously proposed that a potential reason for the failure of NSAIDs to halt the progression of joint disease in rheumatoid arthritis may result from the inhibition of COX 2 during periods of remission (4)
. As iPLA2 drives the onset phase of an acute inflammation but is absent during resolution, we suggest that iPLA2 may represent a novel target for the treatment for rheumatoid arthritis, whose inhibition will prevent the severity in the disease flare but will not alter the natural process of remission.
Received for publication August 19, 2003. Accepted for publication November 21, 2003.
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REFERENCES |
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