Antibiotics may impair hematopoietic recovery after cytotoxic myeloablation.

Antibiotics may impair hematopoietic recovery after cytotoxic myeloablation Patients recovering from myelotoxic chemotherapy require antibiotic treatment to prevent infectious complications, because of their immunocompromised status. Antibiotics such as doxycylin and tetracyclin are known to inhibit matrix metallopro-teinases (MMPs) including MMP-9. 1-3 Recent studies revealed that hematopoietic recovery after administration of the myelo-toxic agent 5-fluorouracil (5-FU) requires MMP-9, also known as gelatinase B. 4 We therefore investigated whether antibiotics such as doxycycline might impair hematopoietic recovery after chemomyeloablation. Mice were treated with doxycycline via the drinking water (30 mg/kg), as described previously. 2 Compared with control mice, treatment with doxycycline impaired the recovery of white blood cells (WBCs) after 5-FU therapy (200 mg/kg intravenously; Figure 1A), similar to MMP-9 deficiency 4 (data not shown). Doxycycline treatment did not affect WBC counts in steady-state conditions (data not shown). Doxycycline is known to inhibit various other MMPs besides MMP-9, including MMP-2 (gelatinase A) and MMP-12 (met-alloelastase), which, similar to MMP-9, is expressed predominantly by hematopoietic cells. 5 However, the role of MMP-2 and MMP-12 in the hematopoietic recovery after chemomyeloabla-tion remains unknown. To evaluate a possible role of MMP-2 and MMP-12, we first performed immunostaining on bone marrow (BM) sections of wild-type (WT) mice, and found that MMP-2 and MMP-12 were diffusely present throughout the BM cavity in stromal and hematopoietic cells, respectively, after 5-FU (Figure 1B,C). We next studied the hematopoietic recovery after 5-FU in mice lacking MMP-2 (MMP-2 Ϫ/Ϫ) or MMP-12 (MMP-12 Ϫ/Ϫ). Because the genetic background of these MMP-deficient lines is not identical, we used these mice not to compare their myeloid recovery quantitatively side-by-side, but to identify qualitatively which of these MMPs participated in hematopoietic recovery after 5-FU. As sensitivity to 5-FU is dependent on the genetic background, we first determined, in pilot experiments, a sublethal dose of 5-FU for each respective background (200 mg/ kg intravenously; not shown). Irrespective of their genetic background, WT mice from all control strains experienced leukopenia at 7 and 11 days after 5-FU, followed by rebound leukocytosis on days 14 and 17, with complete normalization of WBC counts after 2 to 3 weeks (Figure 1D,E). In contrast, WBC recovery after 5-FU was impaired in the absence of MMP-2 or MMP-12 (P Ͻ .05 by analysis of variance [ANOVA]; Figure 1D,E). The defect in hematopoietic recovery of 5-FU–treated MMP-2 Ϫ/Ϫ and MMP-12 Ϫ/Ϫ mice was specific, as their response to the mobilizing agent G-CSF …