An animal model for the study of genetic predisposition in the pathogenesis of middle ear inflammation.

OBJECTIVES: Chronic otitis media with effusion (COME) is the most prevalent inflammatory disease in children and is associated with numerous adverse long-term sequelae. Many factors have been associated with an increased risk of developing COME, one of which may be a genetic predisposition to the disease. To study the role that genetics play in the pathogenesis of COME, we used an animal model to compare the middle ear inflammatory responses in two different strains of rats (Lewis and Fisher). METHODS: In earlier studies, we demonstrated that exposure of the middle ear to endotoxin caused early extensive exudation and, later, goblet cell hyperplasia and mucin hypersecretion. In the present study, the animals were divided into six groups. In each group the animals were given transtympanic injection with gram-positive bacterial cell wall product (peptidoglycan-polysaccharide [PG-PS]). The middle ear bullae were studied at 1 week and 3 weeks after infection, and after systemic reinfection. Comparisons were made of the quantity of mucin exudate by enzyme-linked immunosorbent assay and by histological evaluation of the middle ear epithelial thickness. RESULTS: Our data demonstrate a statistically significant difference in middle ear inflammation and effusion formation between the two genetically different strains of rats. CONCLUSIONS: These data support the hypothesis that the middle ear response to PG-PS may be genetically determined and therefore suggest that genetic predisposition may play a role in the pathogenesis of COME.

Systemic reactivation of otitis media with effusion in a rat model.

OBJECTIVE: This study addresses the interaction of bacterial antigens, specifically peptidoglycan-polysaccharide (PG-PS) and lipopolysaccharide (LPS), in the induction and reactivation of mucoid middle ear effusions. METHODS: Twenty-seven rats underwent eustachian tube obstruction before inoculation of the middle ear bulla with PG-PS. Three weeks later, after resolution of all middle ear effusions, 6 rats were randomly selected and euthanized as the first control group (control I). The remaining 21 animals were randomly assigned to 3 groups that received intravenous injections of Krebs Ringer (control II), PG-PS, and LPS, respectively. These rats were euthanized 2 days after intravenous injection. Middle ear mucin production and histologic changes were measured in all animals. RESULTS: The mean concentrations of mucin were 0.94 +/- 0.52 mg/mL, 0.41 +/- 0.87 mg/mL, 16.33 +/- 3.67 mg/mL, and 1.15 +/- 0.41 mg/mL in the control I, control II, PG-PS, and LPS groups, respectively. Thus the mean concentration of mucin in the middle ear lavage samples was significantly greater in rats that were injected intravenously with PG-PS than in rats in other groups (P < 0.05). Histologic analyses demonstrated a greater degree of goblet cell hyperplasia in the PG-PS group than in other groups. CONCLUSIONS: This is the first animal model of recurring otitis media with effusion in which a systemic injection of PG-PS was used to reactivate a middle ear effusion in rats previously primed with a transtympanic injection of PG-PS. This study suggests that after otitis media with effusion has resolved, it may be reactivated by the presence of bacterial antigens and/or cytokines in the systemic circulation.

Immune System Activation in C3H/HeJBir Mice Exhibiting Spontaneous Perianal Ulceration.

: We report our initial characterization of the immune system in C3H/HeJBir mice that spontaneously develop perianal ulceration. Analysis of lymphokine production by mucosal and systemic lymphoid cells obtained from these mice revealed higher levels of interleukin (IL)4 in supernatants of in vitro stimulated Peyer's patch and mesenteric lymph node cells from C3H/HeJBir mice with severe perianal lesions than from C3H/HeJBir mice with mild perianal lesions or from normal C3H/HeJ mice. Supernatants that contain the highest amounts of IL-4 contain the lowest amounts of interferon (IFN)-γ. Peyer's patches and mesenteric lymph nodes of C3H/HeJBir mice with severe perianal lesions contain approximately four-fold fewer cells; however, inguinal lymph nodes contain up to 25-fold more cells compared with C3H/HeJ mice. These inguinal lymph node cells secrete IL-6, and T cells that produce IL-2 or IFN-γ can be demonstrated. Serum IgE, IgGl, and IgG2a are all increased in C3H/HeJBir mice with severe perianal ulceration. These results show that C3H/HeJBir mice with grossly evident inflammation have activated lymphocytes in both mucosal and systemic lymphoid organs. Understanding mechanisms of lymphocyte activation and regulation in these mice may provide insights into the pathogenesis of perianal ulceration that is often associated with Crohn's disease.

Peristomal pyoderma gangrenosum and inflammatory bowel disease.

Pyoderma gangrenosum (PG) is a debilitating skin disease most often associated with inflammatory bowel disease and is a reportedly rare cause of peristomal ulceration. The lesions of PG rapidly evolve from small, erythematous pustules to deep, painful, pyogenic ulcers within hours to days of onset. Although the behavior and the appearance of the lesions of peristomal PG are diagnostic, a lack of familiarity with PG often leads to misdiagnosis and inappropriate therapy. This study reports four cases of peristomal PG and discusses the 20 previously reported cases in patients with inflammatory bowel disease. Seventy-five percent of patients were female and 67% had Crohn's disease. All patients had colitis, including all of the patients with Crohn's disease, 82% of whom had additional perineal complications. The diagnosis of peristomal PG was based on clinical appearance alone in 83% of cases. The onset of peristomal PG ranged from 2 weeks to 3 years following ostomy. The response to medical therapy was variable. All cases (17 of 17) treated with high-dose corticosteroids and local wound care responded, but five cases required additional therapy. No patient was successfully treated with stoma revision. Risk factors for the development of peristomal PG include Crohn's colitis, female gender, and perineal disease. While most patients respond well to systemic steroids and local wound care, up to one third of patients require long-term medical management.