Rat cytomegalovirus-induced pneumonitis after allogeneic bone marrow transplantation: effective treatment with (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine.
Two antiviral compounds, (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) and 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG), were evaluated for their effects on rat cytomegalovirus (RCMV)-induced interstitial pneumonitis after allogeneic bone marrow transplantation (BMTx). Eight-week-old Brown Norway rats immunosuppressed by a lethal dose of total body irradiation were inoculated with RCMV and received allogeneic bone marrow cells from Lewis rats. Animals were treated with either HPMPC (20 mg/kg of body weight as a single dose) or DHPG (20 mg/kg as two daily doses for 5 days). The effect of antiviral therapy was monitored by measuring RCMV titers in different organs and the histopathologic changes in lungs at 8 to 10 days postinfection. In RCMV-infected allogeneic BMTx recipients, severe diffuse thickening of alveolar septa (6.02 microns) with a diffuse infiltration of mononuclear cells occurred, whereas in the noninfected allogeneic BMTx recipients, the septal width was on the order of 2 microns (P < 0.01). Treatment with DHPG (20 mg/kg in two daily doses for 5 days) resulted in a decrease in virus titers (log10 PFU per gram of tissue) in lungs and spleens from 3.81 +/- 0.34 and 4.29 +/- 1.07 (untreated animals) to 1.26 +/- 0.53 and 3.22 +/- 0.27 (treated animals), respectively. Treatment with HPMPC (20 mg/kg as a single dose) resulted in a complete reduction of virus titers in all organs to below the detection level (P < 0.01). Furthermore, antiviral treatment resulted in a reduction of the alveolar septal width from 6.02 +/- 1.59 microns (untreated animals) to 4.67 +/- 1.70 and 3.32 +/- 0.63 microns after DHPG and HPMPC treatment, respectively. Treatment with HPMPC (20 mg/kg as a single dose) resulted in a complete reduction of virus titers in all organs to below the detection level (P <0.01). Furthermore, antiviral treatment resulted in a reduction of the alveolar septal width from 6.02 +/- 1.59 micrometre (untreated animals) to 4.67 +/- 0.63 micrometre after DHPG and HPMPC treatment, respectively. Furthermore, the influx of mononuclear cells in the alveolar septa was significantly impaired after treatment with HPMPC (P <0.01). We conclude that in the described rat model, HPMPC is highly effective in suppressing RCMV-induced interstitial pneumonitis after allogeneic BMTx.
Department of Medical Microbiology, University of Limburg, Maastricht, The Netherlands.
F S
FS
Stals
A
A
Zeytinoglu
M
M
Havenith
E
E
de Clercq
C A
CA
Bruggeman
D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016026:Bone Marrow Transplantation / Q000502:physiology*; D000077404:Cidofovir; D003587:Cytomegalovirus / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D003596:Cytosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004195:Disease Models, Animal; D015774:Ganciclovir / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D007150:Immunohistochemistry; D008168:Lung / Q000473:pathology; D008297:Male; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016612:Paraffin Embedding; D011024:Pneumonia, Viral / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D051381:Rats; D014916:Whole-Body Irradiation
D000956:Antigens, Viral; D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D003596:Cytosine; C045895:9-((2,3-dihydroxy-1-propoxy)methyl)guanine; D000077404:Cidofovir; D015774:Ganciclovir