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Published on: October 2, 2017
Polyamine transport as a target for treatment of Pneumocystis pneumonia
Chung-Ping Liao1, Otto Phanstiel, Mark E Lasbury
1Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Abstract:
Polyamine levels are greatly increased in alveolar macrophages (AMs) during Pneumocystis pneumonia (PCP), leading to increased production of H(2)O(2), which causes AMs to undergo apoptosis. One of the mechanisms by which polyamine levels in AMs are elevated is enhanced uptake of exogenous polyamines. In this study, the possibility of targeting polyamine uptake as a treatment for PCP was examined. Four anthracene- and one benzene-polyamine conjugates that are potential polyamine transport inhibitors, including N1-anthracen-9-ylmethyl-butane-1,4-diamine; N-(4-aminobutyl)-N-anthracen-9-ylmethylbutane-1,4-diamine; N-[4-(4-aminobutylamino)butyl]-N-anthracen-9-ylmethylbutane-1,4-diamine; N-(4-amino-butyl)-N'-(10-[[4-(4-amino-butylamino)butylamino]-methyl]anthracen-9-ylmethyl)butane-1,4-diamine (44-Ant-44); and benzene-polyamine conjugate N-(4-amino-butyl)-N'-(4-[[4-(4-amino-butylamino)butylamino]-methyl]benzyl)butane-1,4-diamine (44-Bn-44), were tested. Compounds 44-Ant-44 and 44-Bn-44 were found to have a very low toxicity to AMs in vitro and were evaluated for their therapeutic effect on PCP in vivo. Sprague-Dawley rats infected with P. carinii for 28 days were intranasally instilled with 50 microl of a 1 mM solution of 44-Bn-44 or 44-Ant-44 every 2 days. Twenty-one days after initiation of the treatment, three to five rats from each group were sacrificed and examined for lung pathology, organism burden, and apoptosis of AMs. Both 44-Bn-44 and 44-Ant-44 reduced organism burdens; however, only 44-Ant-44 decreased the severity of the infection with reduced lung inflammation, increased clearance of exudates, increased air space, and decreased apoptosis of AMs. 44-Ant-44 also significantly prolonged the survival of treated animals. These results suggest that polyamine uptake is a potential target for treatment of PCP.
Insights
Polyamines increase in Pneumocystis pneumonia (PCP), harming alveolar macrophages (AMs). Targeting polyamine uptake with 44-Ant-44 reduced infection severity and AM apoptosis in rats, suggesting a new PCP treatment strategy.
Area of Science:
- Infectious Diseases
- Immunology
- Pharmacology
Background:
- Pneumocystis pneumonia (PCP) is characterized by elevated polyamine levels in alveolar macrophages (AMs).
- Increased polyamines lead to hydrogen peroxide production, causing AM apoptosis and exacerbating PCP.
- Enhanced uptake of exogenous polyamines contributes to elevated polyamine levels in AMs during PCP.
Purpose of the Study:
- To investigate targeting polyamine uptake as a potential therapeutic strategy for PCP.
- To evaluate the efficacy of novel polyamine-conjugate compounds as inhibitors of polyamine transport.
Main Methods:
- Synthesis and in vitro toxicity assessment of four anthracene- and one benzene-polyamine conjugates.
- In vivo evaluation of promising compounds (44-Ant-44 and 44-Bn-44) in a rat model of Pneumocystis carinii pneumonia (PCP).
- Assessment of lung pathology, organism burden, AM apoptosis, and survival rates following treatment.
Main Results:
- Compounds 44-Ant-44 and 44-Bn-44 demonstrated low toxicity to AMs in vitro.
- Both compounds reduced organism burden in infected rats.
- 44-Ant-44 significantly decreased infection severity, lung inflammation, and AM apoptosis, while increasing air space and prolonging survival.
Conclusions:
- Targeting polyamine uptake represents a promising therapeutic approach for PCP.
- The compound 44-Ant-44 shows significant therapeutic potential for treating PCP by modulating polyamine levels and reducing host cell damage.
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