Abstract
Loss of control in the trafficking of immune cells to the inflamed lung tissue contributes to the pathogenesis of life-threatening acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS). Targeting CXCR7 has been proposed as a potential therapeutic approach to reduce pulmonary inflammation; however, its role and its crosstalk with the two chemokine receptors CXCR3 and CXCR4 via their shared ligands CXCL11 and CXCL12 is not yet completely understood. The present paper aimed to characterize the pathological role of the CXCR3/CXCR4/CXCR7 axis in a murine model of ALI. Lipopolysaccharide (LPS) inhalation in mice resulted in the development of key pathologic features of ALI/ARDS, including breathing dysfunctions, alteration in the alveolar capillary barrier, and lung inflammation. LPS inhalation induced immune cell infiltration into the bronchoalveolar space, including CXCR3+ and CXCR4+ cells, and enhanced the expression of the ligands of these two chemokine receptors. The first-in-class CXCR7 antagonist, ACT-1004-1239, increased levels of CXCL11 and CXCL12 in the plasma without affecting their levels in inflamed lung tissue, and consequently reduced CXCR3+ and CXCR4+ immune cell infiltrates into the bronchoalveolar space. In the early phase of lung inflammation, characterized by a massive influx of neutrophils, treatment with ACT-1004-1239 significantly reduced the LPS-induced breathing pattern alteration. Both preventive and therapeutic treatment with ACT-1004-1239 reduced lung vascular permeability and decreased inflammatory cell infiltrates. In conclusion, these results demonstrate a key pathological role of CXCR7 in ALI/ARDS and highlight the clinical potential of ACT-1004-1239 in ALI/ARDS pathogenesis.
Highlights
Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are life-threatening lung diseases that can be the result of different indirect or direct insults to the lung, such as sepsis, trauma, gastric acid aspiration, and pneumonia, including viral pneumonia, such as SARS-CoV-2-induced pneumonia (Wheeler and Bernard, 2007; Gibson et al, 2020)
Characterization of the consequences of LPS inhalation in DBA/1 mice was conducted to confirm in this experimental animal model (Matute-Bello et al, 2008) the presence of key features defining human ALI/ARDS, namely, breathing dysfunction, increased alveolar capillary barrier permeability, and immune cell infiltrates into the airspaces and the lung tissue
LPS inhalation led to a time-dependent infiltration of CD45+ immune cells into the bronchoalveolar lavage (BAL) compared with control mice, peaking 24 h after LPS challenge (Figure 1C and Supplementary Figure S1)
Summary
Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are life-threatening lung diseases that can be the result of different indirect or direct insults to the lung, such as sepsis, trauma, gastric acid aspiration, and pneumonia, including viral pneumonia, such as SARS-CoV-2-induced pneumonia (Wheeler and Bernard, 2007; Gibson et al, 2020). ALI and ARDS are characterized by increased lung vascular permeability, pulmonary edema, diffuse alveolar damage, and recruitment of inflammatory cells to the lungs resulting in clinical symptoms such as hypoxemia, dyspnea, and even severe acute respiratory failure (Ware and Matthay, 2000). Many chemokines and their receptors, which are key mediators of immune cell trafficking, play a critical role in ALI pathogenesis and in its resolution (Bhatia et al, 2012; Tomankova et al, 2015). Chemokine gradients are established and tightly regulated via complex mechanisms to recruit inflammatory cells to the site of inflammation (Puneet et al, 2005)
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