Characterization of methylated bovine serum albumin-induced allergic inflammation in rats.

An air pouch type allergic inflammation in rats was induced using an insoluble cationic protein, methylated bovine serum albumin (MeBSA), as an antigen. Changes in vascular permeability, local tissue edema, histamine contents in the pouch fluid, and number of infiltrated leukocytes and chemotactic activity in the pouch fluid were analyzed during an 8-hour period after injecting the antigen solution into the air pouch of the immunized and nonimmunized rats. Vascular permeability during the first 30-min interval in the immunized rats was higher than that in the nonimmunized rats, reflecting a higher histamine level in the pouch fluid. However, both the increase in vascular permeability and histamine level in the immunized rats in this period were much lower than those induced by a soluble, noncationic antigen, azobenzenearsonate-conjugated acetyl bovine serum albumin. In the MeBSA-induced allergic inflammation model, a second peak of vascular permeability was induced at 2 h, and local tissue edema formation became apparent at 2 h, reaching a plateau at 4 h. A prominent increase in leukocyte infiltration, especially neutrophils, into the pouch fluid was induced at 4 h in accordance with an increase in chemotactic activity in the pouch fluid. These observations indicate that the acute phase of MeBSA-induced allergic inflammation is characterized by a weak anaphylactic response and a prominent neutrophil infiltration.     

Enhancement of neutrophil infiltration in histidine decarboxylase-deficient mice

The roles of histamine in the anaphylactic increase in vascular permeability and leucocyte infiltration were analysed in an air pouch-type allergic inflammation model in histidine decarboxylase-deficient (HDC^−/−) mice and wild-type mice. In the immunized wild-type mice, histamine content in the pouch fluid and vascular permeability in the anaphylaxis phase were increased by injection of the antigen solution into the air pouch. However, in the immunized HDC^−/− mice, the antigen challenge did not increase histamine content in the pouch fluid and vascular permeability in the anaphylaxis phase. Number of leucocytes (more than 83% are neutrophils) in the pouch fluid 4–24 hr after the antigen challenge in the HDC^−/− mice was significantly higher than that in the wild-type mice. Simultaneous injection of histamine with the antigen solution into the air pouch of the immunized HDC^−/− mice reduced the antigen-induced leucocyte infiltration at 4 hr. Simultaneous injection of the H2 antagonist cimetidine but not the H1 antagonist pyrilamine with the antigen solution into the air pouch of the immunized wild-type mice further increased leucocyte infiltration at 4 hr. The levels of macrophage inflammatory protein-2 at 2 hr and of tumour necrosis factor-α at 4 hr in the pouch fluid of the HDC^−/− mice were significantly higher than those of the wild-type mice. These findings indicate that histamine plays significant roles not only in the anaphylactic increase in vascular permeability via H1 receptors but also in the negative regulation of neutrophil infiltration via H2 receptors in allergic inflammation.     

Leukocyte-Derived Neutrophil Chemotactic Factor-2 Produced by Infiltrated Leukocytes in Allergic Inflammation Model in Rats is Macrophage Inflammatory Protein-2

In the air pouch-type allergic inflammation model in rats, leukocytes collected from the pouch fluid 4 h after the antigen challenge produced proteinaceous chemotactic factors for neutrophils. The leukocytes from the immunized rats produced significantly higher amount of the chemotactic factors than that from the non-immunized rats. The major chemotactic factor, leukocyte-derived neutrophil chemotactic factor (LDNCF)-2, was purified and found to be identical with rat macrophage inflammatory protein (MIP)-2 by N-terminal amino acid sequence analysis. Expression of MIP-2 mRNA was higher in the leukocytes from the immunized rats than that from the non-immunized rats. Possible roles of LDNCF-2 (MIP-2) in neutrophil infiltration in the allergic inflammation is discussed.     

Leukocyte-Derived Neutrophil Chemotactic Factor-2 Produced by Infiltrated Leukocytes in Allergic Inflammation Model in Rats is Macrophage Inflammatory Protein-2

In the air pouch-type allergic inflammation model in rats, leukocytes collected from the pouch fluid 4 h after the antigen challenge produced proteinaceous chemotactic factors for neutrophils. The leukocytes from the immunized rats produced significantly higher amount of the chemotactic factors than that from the non-immunized rats. The major chemotactic factor, leukocyte-derived neutrophil chemotactic factor (LDNCF)-2, was purified and found to be identical with rat macrophage inflammatory protein (MIP)-2 by N-terminal amino acid sequence analysis. Expression of MIP-2 mRNA was higher in the leukocytes from the immunized rats than that from the non-immunized rats. Possible roles of LDNCF-2 (MIP-2) in neutrophil infiltration in the allergic inflammation is discussed.     

Downward regulation of neutrophil infiltration by endogenous histamine without affecting vascular permeability responses in air-pouch-type carrageenin inflammation in rats

The role of histamine in neutrophil infiltration and vascular permeability response in carrageenin air pouch inflammation in rats was examined. Injection of carrageenin solution into an air pouch induced a gradual increase in histamine content in the pouch fluid and histidine decarboxylase activity of pouch wall tissues, with a maximum attained at 24 h. Local administration of the H₂ antagonists cimetidine and famotidine, but not the H₁ antagonist pyrilamine, induced an increase in neutrophil infiltration at 24 h. Both types of histamine antagonists failed to suppress the vascular permeability response. In addition, H₂ antagonists attenuated the inhibitory effect of indomethacin on neutrophil infiltration without affecting the indomethacin-induced suppression of vascular permeability response. These results suggest that histamine produced in the inflammatory locus exerts a downward regulation of neutrophil infiltration through H₂ receptors but does not play any significant role in the vascular permeability response. Furthermore, the inhibition by indomethacin of neutrophil infiltration might be ascribed to the increase in histamine level in the pouch fluid.     

Induction of neutrophil infiltration by rat chemotactic cytokine (CINC) and its inhibition by dexamethasone in rats

In vivo effects of cytokine-induced neutrophil chemotactic factor (CINC) derived from rats on neutrophil infiltration were investigated using an air-pouch-type inflammation model in rats, and effects of dexamethasone on neutrophil infiltration induced by CINC was also examined in order to gain further insight into the mechanism of antiinflammutory activity of glucocorticoids. Injection of CINC into the air pouch made on the dorsum of rats induced a marked infiltration of neutrophils into the pouch fluid but not mononuclear cells and eosinophils during a 30-min interval after the injection. Maximum effect was induced at a dose of 1.4g/pouch. Treatment with dexamethasone 3 h before the injection of CINC suppressed the neutrophil infiltration in a dose-dependent manner, but no complete inhibition was observed. CINC injection into the air pouch of rats that had been sacrificed by bleeding in order to minimize neutroph il infiltration from blood stream also stimulated neutrophil infiltration into the pouch fluid when the carcass was incubated at 37C for 30 min, but the number of infiltrated neutrophils was about 35% of CINC-induced neutrophil infiltration in intact ruts. CINC-induced neutrophil infiltration in the carcass, which is supposed to be a reflection of neutrophil migration from extravascular space in subcutaneous tissues to pouch fluid, was not inhibited by dexamethasone treatment. Therefore, the inhibition of neutrophil infiltration by dexamethasone might be due to inhibition of the extravasation of peripheral neutrophils but not due to inhibition of neutrophil chemotaxis from subcutaneous extravascular space to pouch fluid. These findings suggest that clinical effects of steroidal antiinflammatory drugs on neutrophil infiltration in inflammatory disease is partly due to inhibition of neutrophil extravasation induced by preformed neutrophil chemotactic factors in the inflammatory site.     

Analysis of histamine-producing cells at the late phase of allergic inflammation in rats

To identify histamine-producing cells at the late phase of allergic inflammation, the expression of L-histidine decarboxylase (HDC) was examined in the infiltrating leucocytes in the inflammatory locus. HDC activity and HDC mRNA levels in the infiltrating leucocytes in the pouch fluid of the immunized rats (that were injected with the antigen solution into the air pouch) were increased compared with those in the infiltrating leucocytes of the non-immunized rats. When infiltrating leucocytes collected 8 hr after antigen injection were cultured, histamine production by the cells from the immunized rats was higher than that from the non-immunized rats. In situ hybridization of HDC mRNA revealed that almost all the infiltrating leucocytes of the immunized rats, 4 hr after injection of the antigen, expressed HDC mRNA with high intensity, while those of the non-immunized rats showed only a weak intensity of HDC mRNA. In the immunized rats, approximately 90% of leucocytes infiltrating in the pouch fluid at 4 hr were neutrophils and 8% were monocytes/macrophages. Neither mast cells nor basophils were detected in the infiltrating leucocytes. When rat peritoneal neutrophils were incubated in the presence of 12-O-tetradecanoylphorbol 13-acetate, histamine production was significantly increased. These findings suggest that the leucocytes, mainly neutrophils, infiltrating at the inflammatory locus are responsible for histamine production at the late phase of allergic inflammation.     

A model of persistent antigen-induced chronic inflammation in the rat air pouch

Continuing antigen-induced inflammation was established in a subcutaneous air pouch in rats by recurrent local challenge. The animals were sensitized using bovine serum albumin in Freund's complete adjuvant and were challenged 14 days later by injection of the antigen in a solution containing sodium carboxymethylcellulose into the air pouch to produce allergic inflammation. A single antigenic challenge induced acute inflammation with a predominantly polymorph infiltration in the first 48 h. Later samples showed a low-grade mononuclear response which persisted for 4-5 days. Repeated challenge produced chronic inflammation with an accentuated mononuclear response. Connective tissue activation involving fibronectin and collagen was seen as the inflammation progressed, and this was associated with production of ferritin by mononuclear cells. Discontinuation of challenge injections resulted in resolution of the granuloma. We suggest this model can be used to investigate the mechanisms involved in chronic inflammatory diseases with an immunological component and to evaluate the effects of therapeutic intervention upon chronic allergic inflammation.     

A model of persistent antigen-induced chronic inflammation in the rat air pouch.

Continuing antigen-induced inflammation was established in a subcutaneous air pouch in rats by recurrent local challenge. The animals were sensitized using bovine serum albumin in Freund''s complete adjuvant and were challenged 14 days later by injection of the antigen in a solution containing sodium carboxymethylcellulose into the air pouch to produce allergic inflammation. A single antigenic challenge induced acute inflammation with a predominantly polymorph infiltration in the first 48 h. Later samples showed a low-grade mononuclear response which persisted for 4-5 days. Repeated challenge produced chronic inflammation with an accentuated mononuclear response. Connective tissue activation involving fibronectin and collagen was seen as the inflammation progressed, and this was associated with production of ferritin by mononuclear cells. Discontinuation of challenge injections resulted in resolution of the granuloma. We suggest this model can be used to investigate the mechanisms involved in chronic inflammatory diseases with an immunological component and to evaluate the effects of therapeutic intervention upon chronic allergic inflammation.     

Mechanism underlying acute resident leukocyte disappearance induced by immunological and non-immunological stimuli in rats: evidence for a role for the coagulation system

OBJECTIVE: To investigate the involvement of the fibrinogen-fibrin system in the acute reduction of the resident leukocyte population following pleural inflammation. METHODS: Sensitized and naive rats were injected intrapleurally (i.pl.) with antigen (ovalbumin) and platelet-activating factor (PAF) or bradykinin, respectively. Heparin (0.25 U/cavity), EDTA (80 microg/cavity) and hirudin (1 U/cavity) were injected locally 5 min before challenge, whereas fucoidin was injected intraperitoneally 30 min before stimulation. RESULTS: Antigen challenge led to a rapid reduction in the number of resident leukocytes 30 min post-challenge (from 7.7 +/- 0.4 x 10(6) cells/cavity to 2.3 +/- 0.2 x 106 cells/cavity, n = 6, p < 0.001). The pleural stimulation of naive rats with either PAF or bradykinin also led to a significant decrease in the pleural leukocyte population, which occurred in parallel with the formation of a fibrin meshwork containing captured cells, as attested by electron microscopy. Heparin prevented the drop in the total leukocyte numbers, without modifying either plasma leakage or histamine release at 30 min or the subsequent neutrophil and eosinophil infiltration noted 4 and 24 h post-challenge, respectively. Similarly, hirudin and EDTA prevented the antigen-induced leukocyte disappearance reaction. Heparin also impaired the drop in the pleural leukocyte numbers evoked by PAF and bradykinin. CONCLUSION: Our data show that the pleural resident cell disappearance phenomenon noted early after inflammatory provocation depends on the activation of the fibrinogen-fibrin system, and is not required for the subsequent leukocyte recruitment.     

Increase in Histamine Production by Inflammatory Exudate in the Chronic Phase of Allergic Inflammation in Rats

In the air pouch-type allergic inflammation in rats, we reported that a sustained histamine production in the late phase is induced by a cytokine-like factor, named histamine-production-increasing factor (HPIF) (1). Recently, we found another type of histamine-production-increasing factor in the pouch fluid at the chronic phase of air pouch-type allergic inflammation. Although it did not increase histamine production by itself, it enhanced the HPIF-induced histamine production by rat bone marrow cells. It also increased GM-CSF-induced histamine production. The activity of this factor increased time-dependently from 3 to 7 days after the antigen challenge. Injection of the 5 day pouch fluid sample containing this factor into the pouch 4 h after the antigen challenge increased histamine contents in the pouch fluid at 24 h, indicating that this factor enhances HPIF-induced histamine production in vivo. Biochemical analysis of the 5 day pouch fluid sample indicated that this factor is a heat-labile and trypsin-sensitive protein of which pI value and molecular weight are 7–8 and about 100 kDa, respectively.     

Level of neutrophil chemotactic factor CINC/gro, a member of the interleukin-8 family, associated with lipopolysaccharide-induced inflammation in rats.

Rat cytokine-induced neutrophil chemoattractant (CINC), which is a counterpart of human gro and belongs to the interleukin-8 family, has been quantified by a new sandwich enzyme-linked immunosorbent assay. Administration of lipopolysaccharide (LPS) into an air pouch performed by subcutaneous injection of air caused inflammation and severe neutrophil infiltration. After the LPS injection, changes in the concentration of CINC/gro, chemotactic activity, and the number of neutrophils in the air pouch exudate were determined. The chemotactic activity of neutrophils was augmented before practical neutrophil infiltration. More than half of the chemotactic activity was neutralized by the antisera. The time kinetics of the level of CINC/gro coincided with the changes in chemotactic activity. The maximal level of rat CINC/gro was 85 ng/ml, which is sufficient to cause neutrophil migration in vitro and in vivo as described previously. These data suggest that rat CINC/gro is a functional chemoattractant for neutrophils in LPS-induced inflammation in rats.     

Effect of boldine, secoboldine, and boldine methine on angiotensin II-induced neutrophil recruitment in vivo

Angiotensin-II (Ang-II) has inflammatory activity and is involved in different diseases associated with the cardiovascular system. This study has evaluated the effect of boldine (B), and two phenanthrene alkaloids semisynthesized by us, secoboldine (SB) and boldine methine (BM), on Ang-II-induced neutrophil recruitment. Intraperitoneal administration of 1 nM Ang-II induced significant neutrophil accumulation, which was maximal at 4-8 h. BM inhibited neutrophil infiltration into the peritoneal cavity at 4 h and 8 h by 73% and 77%, respectively, SB at 8 h by 55%, and B had no effect on this response. Although BM inhibited the release of cytokine-inducible neutrophil chemoattractant/keratinocyte-derived chemokine, macrophage inflammatory protein-2 (MIP-2), and platelet-activating factor (PAF) elicited by Ang-II, SB only reduced the release of MIP-2 after 4 h of its administration. Sixty-minute superfusion of the rat mesentery with 1 nM Ang-II induced a significant increase in the leukocyte-endothelial cell interactions and P-selectin up-regulation, which were inhibited by 1 microM BM and SB. The generation of reactive oxygen species (ROS) in endothelial cells stimulated with Ang-II was inhibited significantly by the three alkaloids tested. BM also diminished Ang-II-induced interleukin-8 release from endothelial cells and blocked the PAF receptor on human neutrophils (concentration of the compound needed to produce 50% inhibition value: 28.2 microM). Therefore, BM is a potent inhibitor of Ang-II-induced neutrophil accumulation in vivo. This effect appears to be mediated through inhibition of CXC chemokine and PAF release, ROS scavenging activity, and blockade of the PAF receptor. Thus, it may have potential therapeutic interest for the control of neutrophil recruitment that occurs in inflammation associated with elevated levels of Ang-II.     

Contribution of cytokine-induced neutrophil chemoattractant CINC-2 and CINC-3 to neutrophil recruitment in lipopolysaccharide-induced inflammation in rats

OBJECTIVE: We have estimated the contribution of three types of cytokine-induced neutrophil chemoattractants (CINC-1, -2 and -3) and rat macrophage inflammatory protein (MIP)-1alpha to neutrophil recruitment in the air pouch/ lipopolysaccharide (LPS)-induced inflammation in rats. MATERIALS AND METHODS: Excess amounts of anti-CINC-2, CINC-3 and MIP-1alpha antibodies (Abs), together with LPS (1 microg/ml), were injected into the preformed air pouch of rats. Chemokine levels and chemotactic activity in the pouch fluid were measured using enzyme-linked immunosorbent assay and multiwell-type Boyden chambers in vitro, respectively. RESULTS: Excess amounts of the Abs significantly neutralized CINC-1 and almost completely neutralized CINC-2, CINC-3 and MIP-1 alpha in the pouch fluid, and a significant suppression (about 60% inhibition) of neutrophil infiltration by the Abs was found. In agreement with the in vivo results, in vitro neutralization experiments demonstrated that complete neutralization of CINCs and MIP-1alpha by the Abs resulted in a marked suppression (73% inhibition) of chemotactic potency of 8-h pouch fluid (exudate) from LPS-treated rats. On the other hand, treatment with anti-CINC-2, CINC-3 or MIP-1alpha Ab alone resulted in 48%, 34% or 10% inhibition, respectively, of chemotactic activity of the 8-h exudate. CONCLUSIONS: Our results suggest that CINC-2, a novel rat CXC chemokine and CINC-3 play an important role in neutrophil recruitment in the rat air pouch/LPS-induced inflammation.     

Recurrence of an allergic inflammation of air-pouch type in rats and possible participation of prostaglandin E2

The recurrence of allergic inflammation, as examined by exudate accumulation, infiltration of polymorphonuclear leukocytes into the exudate, edema formation, vascular permeability and prostaglandin E2 levels in the exudate, was induced by injecting the antigen, azobenzene arsonate-conjugated acetyl bovine serum albumin, into the capsule of the proliferative granulation tissue which had been formed by the first-time antigenic challenge injection into an air pouch in the dorsum of the sensitized rat. The recurrence of the allergic inflammation 4 and 24 h after the antigenic challenge was inhibited dose-dependently by treatment with cyclooxygenase inhibitors, suggesting the possible participation of cyclooxygenase products, especially prostaglandin E2. The difference in the allergic inflammatory responses induced by the first-time antigenic challenge and the second-time antigenic challenge was discussed from the viewpoint of chemical mediators.     

Attenuation of folic acid-induced renal inflammatory injury in platelet-activating factor receptor-deficient mice

Platelet-activating factor (PAF), a potent lipid mediator with various biological activities, plays an important role in inflammation by recruiting leukocytes. In this study we used platelet-activating factor receptor (PAFR)-deficient mice to elucidate the role of PAF in inflammatory renal injury induced by folic acid administration. PAFR-deficient mice showed significant amelioration of renal dysfunction and pathological findings such as acute tubular damage with neutrophil infiltration, lipid peroxidation observed with antibody to 4-hydroxy-2-hexenal (day 2), and interstitial fibrosis with macrophage infiltration associated with expression of monocyte chemoattractant protein-1 and tumor necrosis factor-alpha in the kidney (day 14). Acute tubular damage was attenuated by neutrophil depletion using a monoclonal antibody (RB6-8C5), demonstrating the contribution of neutrophils to acute phase injury. Macrophage infiltration was also decreased when treatment with a PAF antagonist (WEB2086) was started after acute phase. In vitro chemotaxis assay using a Boyden chamber demonstrated that PAF exhibits a strong chemotactic activity for macrophages. These results indicate that PAF is involved in pathogenesis of folic acid-induced renal injury by activating neutrophils in acute phase and macrophages in chronic interstitial fibrosis. Inhibiting the PAF pathway might be therapeutic to kidney injury from inflammatory cells.     

Comparative effects of tetrandrine and berbamine on subcutaneous air pouch inflammation induced by interleukin-1, tumour necrosis factor and platelet-activating factor

The effects of the bisbenzylisoquinoline alkaloids tetrandrine and berbamine on the action of IL-1, TNF and PAF were investigated in the rat subcutaneous air pouch model of inflammation. Both compounds were equipotent in the suppression of leukocyte infiltration into air pouches induced by IL-1 and TNF, with ED₅₀ values in the range 20–30 mg/kg/3 days. Both were also equiptent in suppression of PMN infiltration induced by PAF with ED₅₀ values in the same range as that for IL-1 and TNF. However, tetrandrine was more potent than berbamine as a suppressant of PAF-induced MNC infiltration, but much less potent than berbamine in carageenen-induced PMN infiltration. These results suggest that these bisbenzylisoquinolines may have value in the therapy of chronic inflammatory diseases where IL-1, TNF and PAF have a role in pathogenesis.     

Blockade of proteinase-activated receptor 4 inhibits neutrophil recruitment in experimental inflammation in mice

Objective and design

The activation of proteinase-activated receptors (PARs) has been implicated in the development of important hallmarks of inflammation, including in vivo leukocyte recruitment; however, its role in the regulation of leukocyte migration in response to inflammatory stimuli has not been elucidated until now. Here, we examined the effects of the PAR4 antagonist YPGKF-NH 2 (tcY-NH₂) on neutrophil recruitment in experimentally induced inflammation.

Methods

BALB/c mice were intrapleurally injected with tcY-NH₂ (40 ng/kg) prior to intrapleural injection of carrageenan (Cg) or neutrophil chemoattractant CXCL8; the number of infiltrating neutrophils was evaluated after 4 h, and KC production was assessed at different times after Cg injection. Neutrophil adhesion and rolling cells were studied using a brain circulation preparation 4 h after the Cg or CXCL8 challenge in tcY-NH₂-treated mice.

Results

PAR4 blockade inhibited CXCL8- and Cg-induced neutrophil migration into the pleural cavity of BALB/c mice and reduced neutrophil rolling and adherence. Surprisingly, PAR4 blockade increased the level of KC in response to carrageenan.

Conclusion

These results demonstrated that PAR4 blockade impairs neutrophil migration in vivo, suggesting that PAR4 plays an important role in the regulation of inflammation, at least in part because of its ability to inhibit the actions of the neutrophil chemoattractant CXCL8.     

Changes in pulmonary function and parasite burden in rats infected with Strongyloides venezuelensis concomitant with induction of allergic airway inflammation

The prevalence of allergic diseases such as asthma has increased markedly over the past few decades. To evaluate the possible mutual influence of helminth infection and allergy, the combined effects of experimental allergic airway inflammation and infection with Strongyloides venezuelensis on various parasitological and inflammatory indices were evaluated in the rat. A challenge of immunized rats with aerosolized ovalbumin (OVA) resulted in eosinophilic inflammation that peaked 48 h after the challenge and was accompanied by airway hyperresponsiveness (AHR) to an intravenous acetylcholine challenge. S. venezuelensis infection concomitant with an OVA challenge of immunized rats resulted in prolonged pulmonary inflammation with increased eosinophil infiltration in bronchoalveolar lavage fluid but not in the lung tissue. These rats also showed a significant parasite burden reduction, especially during parasite migration through the lungs. However, the fecundity rates of worms that reached the intestine were similar in allergic and nonallergic animals. Despite airway inflammation, the increased responsiveness of the airways in the experimental asthma model was suppressed during parasite migration through the lungs (2 days). In contrast, parasite-induced AHR was unchanged 5 days after infection in immunized and challenged rats. In conclusion, infection with S. venezuelensis interfered with the onset of AHR following an antigen challenge of immunized rats. The ability of parasites to switch off functional airway responses is therapeutically relevant because we may learn from parasites how to modulate lung function and, hence, the AHR characteristic of asthmatic patients.     

Inflammation induced by bacterial cell wall fragments in the rat air pouch. Comparison of rat strains and measurement of arachidonic acid metabolites.

Streptococcal cell wall fragments, suspended in phosphate-buffered saline, were injected into a preformed subcutaneous air pouch in rats. The advantage of the air pouch model is the capacity for quantitation of exudative, cellular, and proliferative responses and soluble mediators. Accumulation of pouch fluid containing many leukocytes occurred during the first 3 days. Granulation tissue separable from the surrounding subcutaneous tissue developed by 6 days. Immunofluorescence and immunoperoxidase staining showed the presence of cell walls in inflammatory cells both in pouch fluid and in pouch tissue. Histologic features of this inflammation included an acute exudative phase with a predominantly neutrophil infiltration followed by a chronic phase characterized by fibroblast proliferation, formation of blood vessels, and infiltration with mononuclear cells. The lining of the pouch before injection of cell wall developed morphologic features of synovial membrane, which became more evident during the chronic phase of induced inflammation. Outbred Sprague-Dawley and inbred Lewis rats developed more pouch fluid, cell numbers in the pouch fluid, and granulation tissue than inbred Buffalo rats. The arachidonic acid metabolites, prostaglandin E2 and leukotriene B4, were measured in the pouch fluid, and more of each was produced in the Lewis than in the Buffalo strain. These measurements of inflammation are consistent with the relative susceptibility of these strains to cell-wall-induced arthritis. This model of inflammation can be used in the examination of the regulatory mechanisms of evolving chronic inflammation.