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Alterations in rat pulmonary macrophage function by the immunosuppressive agents cyclosporine, azathioprine, and
Abstract:
Disturbances of the immune response of the lung induced by the action of immunosuppressive agents on the functional abilities of rat pulmonary alveolar macrophages (PAM) were analyzed following in vitro incubation or in vivo administration (for 30 days) of cyclosporinea, (CsA) azathioprine (Az) or prednisolone (Pr). Two major parameters were analyzed: oxygen consumption and superoxide release as indices of the overall state of oxygen metabolism of these cells reflecting the integrity of PAM oxidative mechanisms of microbicidal activity, and chemotaxis, an event clinically important for normal defense to infection. In vitro incubation with cyclosporine at concentrations as low as 10(-9) M caused a 52% inhibition of PAM superoxide release, but Az had no effect at concentrations up to 10(-6) M. Prednisolone caused a 38% inhibition of superoxide release; comparable levels of inhibition with Pr required concentrations at least 10-fold greater than with cyclosporine. Further experiments indicated that cyclosporine induced a 40% inhibition after contact with PAM for only 30 min. In vivo experiments indicated that cyclosporine (5 mg/kg), Az (20 mg/kg), or Pr (2 or 0.5 mg/kg) administered intraperitoneally had no effect on the number of PAM available for host defense, PAM oxygen consumption, or PAM superoxide release. However, PAM from cyclosporine-treated animals demonstrated complete inhibition of active migration or chemotaxis in modified Boyden chambers upon incubation with formylmethionyl-leucyl-phenylalanine (FMLP). The effect was apparently dampened by simultaneous administration of Pr with cyclosporine. These experiments suggest that with the exception of a marked effect on chemotaxis the in vivo effects of physiologic amounts of cyclosporine on PAM function are modest compared with the marked depression after in vitro addition.
Insights
Cyclosporine significantly impairs pulmonary alveolar macrophage (PAM) chemotaxis in vivo, while in vitro, it inhibits superoxide release. Other immunosuppressants like azathioprine and prednisolone showed less impact on these key immune functions.
Area of Science:
- Immunology
- Pharmacology
- Cell Biology
Background:
- Pulmonary alveolar macrophages (PAMs) are crucial for lung immune defense.
- Immunosuppressive agents can alter immune cell function, potentially compromising host defense.
- Understanding the impact of immunosuppressants on PAMs is vital for managing infections in immunocompromised patients.
Purpose of the Study:
- To analyze the effects of immunosuppressive agents (cyclosporine, azathioprine, prednisolone) on rat PAM function.
- To investigate both in vitro and in vivo impacts on cellular metabolism and migration.
- To assess key parameters of PAM oxidative mechanisms and chemotaxis.
Main Methods:
- In vitro incubation and in vivo administration of cyclosporine (CsA), azathioprine (Az), and prednisolone (Pr) to rats.
- Measurement of oxygen consumption and superoxide release as indicators of oxidative metabolism.
- Assessment of PAM chemotaxis using modified Boyden chambers with formylmethionyl-leucyl-phenylalanine (FMLP).
Main Results:
- In vitro, cyclosporine markedly inhibited superoxide release at low concentrations (10(-9) M), while prednisolone had a lesser effect.
- In vivo, CsA, Az, and Pr did not significantly alter PAM oxygen consumption or superoxide release.
- In vivo, cyclosporine administration led to complete inhibition of PAM chemotaxis, an effect partially reduced by co-administration of prednisolone.
Conclusions:
- In vivo, cyclosporine exhibits a potent inhibitory effect on PAM chemotaxis, a critical component of infection defense.
- In vitro, cyclosporine demonstrates significant inhibition of PAM superoxide release.
- The in vivo functional effects of physiological cyclosporine doses on PAMs are modest, except for a pronounced impact on chemotaxis.