Figure 2.
Organ damage parameters are improved in SCD mice after dietary iron restriction. (A) Gross spleen and liver weights are reduced in IRD group compared with Ctrl group. (N = 5) (B) Leukocyte infiltration in lung tissue, quantified by H&E staining, is decreased in IRD treated SCD mice. Low-magnification scale bar (left), 500 μm; high-magnification scale bar (right), 50 μm. (N = 5) (C) H&E staining of liver tissue; area within dashed line shows leukocyte infiltration and necrosis. Scale bar, 100 μm. (D) Liver necrosis, leukocyte infiltration, and fibrosis are all reduced in IRD mice. (N = 4-5) (E) Liver enzymes (alanine aminotransferase and aspartate aminotransferase), total bilirubin concentration, and direct bilirubin concentration from sera of Ctrl and IRD mice. (N = 10-15) (F) Left: representative images of duodenal villi with either H&E, anti-claudin 3 or anti-junctional adhesion molecule A (JAM-A) immunohistology staining in Ctrl and IRD treated SCD mice. H&E scale bar, 50 μm; immunohistology scale bar 20 μm. Right: quantification of intestinal inflammation or percentage of positive stained area. (N = 5) (G) Concentration of FITC-Dextran in serum of IRD mice is significantly lower than Ctrl mice. (N = 7) Dashed line represents levels in the healthy SA mice. (H) Bacterial load measured by Pan-bac quantitative reverse transcription polymerase chain reaction, in fecal samples normalized by the weight of fecal samples. (N = 4-5) Dashed line represents levels in the healthy SA mice. (I) Bacterial Firmicutes/Bacteroidetes ratio of fecal samples from Ctrl and IRD treated SCD mice. (N = 4-5) Dashed line represents levels in the healthy SA mice. (J) Quantification of sera TLR2 ligands activity in Ctrl and IRD treated SCD mice. (N = 5) Dashed line represents levels in the healthy SA mice. (K) Working model. Top: Excess dietary iron expands the proliferation of bacteria (red arrow indicates direct impact from iron) and increases gut permeability (red arrow) which allows the translocation of microbial compounds to internal organs (dashed arrow indicates indirect impact from iron); in parallel, excess iron is absorbed and deposited into organs (red arrow); together lead to exacerbation of neutrophil aging, hemolysis, vaso-occlusion, and organ damage. Bottom: dietary iron restriction reduces bacterial proliferation and ameliorates gut permeability, and consequently decreasing the translocation of microbial compounds and limiting systemic iron levels. Collectively, neutrophil aging, hemolysis, vaso-occlusion, and organ damage are found at lower rates. ∗P < .05, ∗∗P < .01, ∗∗∗P <.001.

Organ damage parameters are improved in SCD mice after dietary iron restriction. (A) Gross spleen and liver weights are reduced in IRD group compared with Ctrl group. (N = 5) (B) Leukocyte infiltration in lung tissue, quantified by H&E staining, is decreased in IRD treated SCD mice. Low-magnification scale bar (left), 500 μm; high-magnification scale bar (right), 50 μm. (N = 5) (C) H&E staining of liver tissue; area within dashed line shows leukocyte infiltration and necrosis. Scale bar, 100 μm. (D) Liver necrosis, leukocyte infiltration, and fibrosis are all reduced in IRD mice. (N = 4-5) (E) Liver enzymes (alanine aminotransferase and aspartate aminotransferase), total bilirubin concentration, and direct bilirubin concentration from sera of Ctrl and IRD mice. (N = 10-15) (F) Left: representative images of duodenal villi with either H&E, anti-claudin 3 or anti-junctional adhesion molecule A (JAM-A) immunohistology staining in Ctrl and IRD treated SCD mice. H&E scale bar, 50 μm; immunohistology scale bar 20 μm. Right: quantification of intestinal inflammation or percentage of positive stained area. (N = 5) (G) Concentration of FITC-Dextran in serum of IRD mice is significantly lower than Ctrl mice. (N = 7) Dashed line represents levels in the healthy SA mice. (H) Bacterial load measured by Pan-bac quantitative reverse transcription polymerase chain reaction, in fecal samples normalized by the weight of fecal samples. (N = 4-5) Dashed line represents levels in the healthy SA mice. (I) Bacterial Firmicutes/Bacteroidetes ratio of fecal samples from Ctrl and IRD treated SCD mice. (N = 4-5) Dashed line represents levels in the healthy SA mice. (J) Quantification of sera TLR2 ligands activity in Ctrl and IRD treated SCD mice. (N = 5) Dashed line represents levels in the healthy SA mice. (K) Working model. Top: Excess dietary iron expands the proliferation of bacteria (red arrow indicates direct impact from iron) and increases gut permeability (red arrow) which allows the translocation of microbial compounds to internal organs (dashed arrow indicates indirect impact from iron); in parallel, excess iron is absorbed and deposited into organs (red arrow); together lead to exacerbation of neutrophil aging, hemolysis, vaso-occlusion, and organ damage. Bottom: dietary iron restriction reduces bacterial proliferation and ameliorates gut permeability, and consequently decreasing the translocation of microbial compounds and limiting systemic iron levels. Collectively, neutrophil aging, hemolysis, vaso-occlusion, and organ damage are found at lower rates. ∗P < .05, ∗∗P < .01, ∗∗∗P <.001.

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