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. 2021 Nov 5;12:748740. doi: 10.3389/fphar.2021.748740

FIGURE 5.

FIGURE 5

Antagonism of CXCR7 reduces LPS-induced ALI/ARDS. Treatment with the CXCR7 antagonist ACT-1004-1239 significantly reduced LPS-induced breathing pattern alteration (A), alveolar–capillary barrier permeability (B), and immune cell infiltrates in the bronchoalveolar space (C) compared with vehicle-treated-LPS exposed mice. Mice were treated with vehicle (LPS-vehicle; black) or ACT-1004-1239 (100 mg/kg, LPS-ACT-1004-1239) orally, twice daily, starting 1 h prior to LPS challenge (preventive setting; LPS-ACTPrev; red) or 3 h after LPS challenge (therapeutic setting; LPS-ACTTher; hatched bar). Control mice were treated with vehicle and inhaled NaCl 0.9% (NaCl-vehicle; white). (A) Preventive treatment with ACT-1004-1239 reduced the LPS-induced breathing pattern alteration, measured by the calculated enhanced pause (Penh) using whole-body plethysmography in conscious unrestrained mice over a period of 6 h following LPS inhalation. Results are expressed as the mean percentage Penh area under the curve (AUC) normalized to the baseline ± SEM (n = 8 mice per group). ****p < 0.0001 using two-way ANOVA, followed by Dunnett’s multiple comparisons test versus LPS-vehicle-treated mice. (B) Preventive and therapeutic treatment with ACT-1004-1239 reduced alveolar–capillary barrier permeability, measured by a reduction in total protein concentration in BAL supernatant 48 h after LPS challenge (n = 7–16 mice per LPS-challenged groups; n = 6 NaCl-vehicle control mice). Results are expressed as mean + SEM. *p < 0.05, **p < 0.01 versus LPS-vehicle-treated mice using one-way ANOVA followed by Dunnett’s multiple comparisons test. (C) Preventive and therapeutic treatment with ACT-1004-1239 reduced immune cell infiltrates in the BAL, measured by flow cytometry 48 h after LPS challenge (n = 7–16 mice per LPS-challenged groups; n = 6 NaCl-vehicle control mice). Results are expressed as mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 versus LPS-vehicle-treated mice using two-way ANOVA followed by Dunnett’s multiple comparisons test. The gating strategy for all immune populations is illustrated in Supplementary Figures S1A,B.