Neutrophilic inflammation during lung development disrupts elastin assembly and predisposes adult mice to COPD

Benjamin, John T.; Plosa, Erin J.; Sucre, Jennifer M.S.; Meer, Riet van der; Dave, Shivangi; Gutor, Sergey; Nichols, David S.; Gulleman, Peter M.; Jetter, Christopher S.; Han, Wei; Xin, Matthew K.; Dinella, Peter C.; Catanzarite, Ashley; Kook, Seunghyi; Dolma, Kalsang; Lal, Charitharth Vivek; Gaggar, Amit; Blalock, J. Edwin; Newcomb, Dawn C.; Richmond, Bradley W.; Kropski, Jonathan A.; Young, Lisa R.; Guttentag, Susan H.; Blackwell, Timothy S.

doi:10.1172/jci139481

Cited by 61 publications

(35 citation statements)

References 71 publications

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“…The use of 95% FiO 2 during P1–P4 (saccular stage of lung development) is high. The main reason to restrict the hyperoxia exposure to the first 4 postnatal days was to restrict the hyperoxia exposure during the saccular stage of lung development in mice ( 24 ). This corresponds to 26–36 weeks in human lung development ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

Effect of sex chromosomes versus hormones in neonatal lung injury

Grimm¹,

Dong²,

Zhang³

et al. 2021

JCI Insight

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The main mechanisms underlying sexually dimorphic outcomes in neonatal lung injury are unknown. We tested the hypothesis that hormonal-or sex chromosomemediated mechanisms interact with hyperoxia exposure to impact injury and repair in the neonatal lung. To distinguish sex differences caused by gonadal hormones versus sex chromosome complement (XX versus XY), we used the four core genotypes (FCG) mice and exposed them to hyperoxia (95% FiO2, PND1-4: saccular stage) or room air. This model generates XX and XY mice that each have either testes (with Sry, XXM or XYM) or ovaries (without Sry, XXF or XYF). Lung alveolarization and vascular development were more severely impacted in XYM and XYF compared to XXF and XXM mice. Cell cycle related pathways were enriched in the gonadal or chromosomal females, while muscle related pathways were enriched in the gonadal males, and immune-response related pathways were enriched in chromosomal males. Female gene signatures showed a negative correlation with human patients that developed BPD or needed oxygen therapy at 28 days. These results demonstrate that, chromosomal sex and not gonadal sex impacted the response to neonatal hyperoxia exposure. The female sex chromosomal complement was protective and could mediate sex-specific differences in the neonatal lung injury.

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Section: Discussionmentioning

confidence: 99%

Effect of sex chromosomes versus hormones in neonatal lung injury

Grimm¹,

Dong²,

Zhang³

et al. 2021

JCI Insight

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“…There is also increasing evidence that NE is a key mediator in BPD, as NE is elevated in BPD airways [129] and has increased enzymatic activity on the surface of neutrophil exosomes obtained from tracheal aspirate of infants with BPD [47]. A recent study using a transgenic mouse model for NFκB activation in the airway found that sublethal inflammation from NE instillation during the saccular stage of lung development, but not during the alveolar stage of development, resulted in a BPD-like lung phenotype of enlarged simplified alveoli, while neutrophil-depleted mice showed normal alveolar structure [130]. NE was also found to be elevated in airways of the mice with lung disease, strongly suggesting that excess NE proteolytic activity leads to aberrant lung development.…”

Section: Ne and Bronchopulmonary Dysplasiamentioning

confidence: 99%

Neutrophil Elastase and Chronic Lung Disease

2021

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Neutrophil elastase (NE) is a major inflammatory protease released by neutrophils and is present in the airways of patients with cystic fibrosis (CF), chronic obstructive pulmonary disease, non-CF bronchiectasis, and bronchopulmonary dysplasia. Although NE facilitates leukocyte transmigration to the site of infection and is required for clearance of Gram-negative bacteria, it also activates inflammation when released into the airway milieu in chronic inflammatory airway diseases. NE exposure induces airway remodeling with increased mucin expression and secretion and impaired ciliary motility. NE interrupts epithelial repair by promoting cellular apoptosis and senescence and it activates inflammation directly by increasing cytokine expression and release, and indirectly by triggering extracellular trap release and exosome release, which magnify protease activity and inflammation in the airway. NE inhibits innate immune function by digesting opsonins and opsonin receptors, degrading innate immune proteins such as lactoferrin, and inhibiting macrophage phagocytosis. Importantly, NE-directed therapies have not yet been effective in preventing the pathologic sequelae of NE exposure, but new therapies are being developed that offer both direct antiprotease activity and multifunctional anti-inflammatory properties.

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“…Previous studies have demonstrated that an i.p. injection of anti-ly6G antibody in mice resulted in successful depletion of circulating neutrophils as examined by flow cytometry [ 78 , 79 , 80 ]. Thus, to transiently deplete NPs in vivo, a group of mice was injected (i.p.)…”

Section: Methodsmentioning

confidence: 99%

Maternal Neutrophil Depletion Fails to Avert Systemic Lipopolysaccharide-Induced Early Pregnancy Defects in Mice

Panja¹,

Benjamin²,

Paria³

2021

IJMS

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Maternal infection-induced early pregnancy complications arise from perturbation of the immune environment at the uterine early blastocyst implantation site (EBIS), yet the underlying mechanisms remain unclear. Here, we demonstrated in a mouse model that the progression of normal pregnancy from days 4 to 6 induced steady migration of leukocytes away from the uterine decidual stromal zone (DSZ) that surrounds the implanted blastocyst. Uterine macrophages were found to be CD206+ M2-polarized. While monocytes were nearly absent in the DSZ, DSZ cells were found to express monocyte marker protein Ly6C. Systemic endotoxic lipopolysaccharide (LPS) exposure on day 5 of pregnancy led to: (1) rapid (at 2 h) induction of neutrophil chemoattractants that promoted huge neutrophil infiltrations at the EBISs by 24 h; (2) rapid (at 2 h) elevation of mRNA levels of MyD88, but not Trif, modulated cytokines at the EBISs; and (3) dose-dependent EBIS defects by day 7 of pregnancy. Yet, elimination of maternal neutrophils using anti-Ly6G antibody prior to LPS exposure failed to avert LPS-induced EBIS defects allowing us to suggest that activation of Tlr4-MyD88 dependent inflammatory pathway is involved in LPS-induced defects at EBISs. Thus, blocking the activation of the Tlr4-MyD88 signaling pathway may be an interesting approach to prevent infection-induced pathology at EBISs.

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Neutrophilic inflammation during lung development disrupts elastin assembly and predisposes adult mice to COPD

Cited by 61 publications

References 71 publications

Effect of sex chromosomes versus hormones in neonatal lung injury

Effect of sex chromosomes versus hormones in neonatal lung injury

Neutrophil Elastase and Chronic Lung Disease

Maternal Neutrophil Depletion Fails to Avert Systemic Lipopolysaccharide-Induced Early Pregnancy Defects in Mice

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