Impairment of granulomatous inflammatory response to Histoplasma capsulatum by inhibitors of angiotensin-converting enzyme

Abstract

Systemic infection with Histoplasma capsulatum induced a granulomatous inflammatory response in the lymphoreticular organs of C57BL/6 mice that was associated with elevated levels of angiotensin-converting enzyme (ACE) in the spleens. To determine the influence of ACE on the granulomatous response, either captopril or MK 421, two inhibitors of ACE, were administered intraperitoneally to mice 6 h after intravenous injection of H. capsulatum and then daily for 1 week. Each ACE inhibitor sharply reduced ACE activity in the spleens of infected mice. Both drugs worsened the clinical severity of infection and significantly increased the growth of H. capsulatum in livers and spleens of mice infected for 1 week. The histopathological changes in mice given captopril were more severe, with massive infiltrates of macrophages in proximity to large aggregates of yeasts. Conversely, the administration of captopril for 2 weeks during the resolving phases of infection did not slow the healing of the granulomatous lesions, nor did it provoke a relapse of infection. Captopril did not promote the growth of H. capsulatum in artificial medium. This drug was not cytotoxic to peripheral blood leukocytes or to splenic leukocytes from normal and infected mice. Administration of captopril to normal mice for 1 week did not depress the response of splenocytes of concanavalin A or to phytohemagglutinin, nor did it diminish delayed-type hypersensitivity responses in vivo. Finally, captopril did not augment the growth of H. capsulatum within macrophages. Our results suggest that ACE may participate in the regulation of the granulomatous inflammatory response to H. capsulatum and that ACE inhibition impairs the protective effects of granulomatous inflammation during acute H. capsulatum infection.

Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Antagonists in Experimental Myocarditis

“…In yet another paper the granulomatous response to Histoplasma capsulatum was modulated by administration of captopril with different findings from any of those reported above. With ACE inhibition present during the early stages of the infection, the clinical severity of infection and the histopathologic changes in mice were significantly worsened and the growth of the yeast in livers and spleens was increased [77]. If captopril was first administered later during the resolution phase of the infection, there was no effect on the healing of the granulomas, but the drug did not cause a relapse of infection.…”

Angiotensin-converting enzyme: new concepts concerning its biological role

“…On the other hand, intestinal ACE, which is present in high concentration on the microvilli (Defendini et al, 1983;Ward et al, 1980) and may, by the generation of All, be involved in fluid and sodium absorption (Crocker & Munday, 1970), or function as a digestive peptidase (Yoshioka et al, 1987), is vulnerable to inhibition by orally active agents (Sakaguchi et al, 1988;Stevens et al, 1988), although this does not appear to have any pathophysiological consequences (Gavras & Gavras, 1988). Where ACE and the RAS are associated with the immune system, the administration of ACE inhibitors results in suppression of granulomatous inflammation, which was beneficial when associated with a nonreplicating antigen such as schistosoma eggs (Weinstock & Boros, 1981) or BCG inoculum (Schrier et al, 1982), but worsened the severity of acute infection with the yeast Histoplasma capsulatum (Deepe et al, 1985). Lastly, ovarian ACE may be inhibited by orally active ACE inhibitors, since in the ovary there is no barrier comparable to the blood-testis barrier (Richards, 1980).…”

Single-cell profiling identifies ACE+granuloma macrophages as a non-permissive niche for intracellular bacteria during persistentSalmonellainfection

“…In addition, we tested to see if inhibition of ACE enzymatic activity affects S Tm tissue persistence by infecting 129×1/SvJ mice with WT S Tm for 1 month and then treating them either with saline control or the ACE inhibitor captopril, 150 mg/kg/day intraperitoneally, for 7 days. This dose of captopril was previously shown to abolish approximately 95% of splenic ACE enzymatic activity in mice infected with Histoplasma capsulatum and is 30-50 fold higher than the maximum daily captopril dose used in treating cardiovascular disease in humans(65). We observed no significant difference in splenic bacterial levels from captopril treatment during persistent S Tm infection in vivo (Fig.…”