CXCR2/CXCR2 ligand biological axis impairs alveologenesis during dsRNA-induced lung inflammation in mice.
The histologic phenotype of bronchopulmonary dysplasia (BPD) is characterized by decreased alveolization and is preceded by infiltration of activated neutrophils into the lung that can lead to sustained lung injury and potential interruption of normal lung development. Potential pathogens triggering early neutrophil influx include either prenatal or postnatal exposure to bacteria or viruses. Specific mechanisms recruiting neutrophils to the lung and subsequently decreasing alveolization during virus-induced lung inflammation and injury have not been fully elucidated. Because CXC chemokines, such as CXCL1 and CXCL2/3 acting through their putative receptor, CXCR2, are potent neutrophil chemoattractants, the authors investigated their role in dsRNA-induced lung injury and decreased alveolization, in which dsRNA (poly IC) is a well-described synthetic agent mimicking acute viral infection. Intratracheal dsRNA led to significant increases in neutrophil infiltration and lung injury at 72 hours and to decreased alveolization at 5 days after dsRNA exposure in newborn (10 days old) BALB/c mice, when compared with controls treated and not treated with ssRNA (poly C). Expression of CXCL1 and CXCR2 paralleled neutrophil recruitment to the lung and preceded the decrease in alveolization. Inhibition of CXCR2/CXCR2 ligand interaction by pretreating dsRNA-exposed mice with an anti-CXCR2 neutralizing antibody significantly attenuated neutrophil sequestration and lung injury, and preserved normal alveolization. These findings demonstrate that the CXCR2/CXCR2 ligand biologic axis plays an important role during the pathogenesis of dsRNA-induced lung injury and decreased alveolization and may be relevant to the pathogenesis of BPD.
Londhe
Vedang A
VA
Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1786, USA.
Belperio
John A
JA
Keane
Michael P
MP
Burdick
Marie D
MD
Xue
Ying Ying
YY
Strieter
Robert M
RM
D000818:Animals; D001483:Base Sequence; D001992:Bronchoalveolar Lavage Fluid; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D011014:Pneumonia / Q000139:chemically induced / Q000473:pathology*; D011650:Pulmonary Alveoli / Q000473:pathology*; D012330:RNA, Double-Stranded / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D023062:Receptors, Interleukin-8A / Q000235:genetics; D023063:Receptors, Interleukin-8B / Q000378:metabolism / Q000502:physiology*
D017931:DNA Primers; D008024:Ligands; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B