Nfib hemizygous mice are protected from hyperoxic lung injury and death

Abstract

Nuclear Factor I (Nfi) genes encode transcription factors essential for the development of organ systems including the lung. Nfib null mice die at birth with immature lungs. Nfib hemizygous mice have reduced lung maturation with decreased survival. We therefore hypothesized that these mice would be more sensitive to lung injury and would have lower survival to hyperoxia. Adult Nfib hemizygous mice and their wild‐type (Wt) littermates were exposed to 100% O2 for 89, 80, 72 and 66 h for survival studies with lung outcome measurements at 66 h. Nfib hemizygous and Wt controls were also studied in RA at 66 h. Cell counts and cytokines were measured in bronchoalveolar lavage (BAL); lung sections examined by histopathology; lung angiogenic and oxidative stress gene expression assessed by real‐time PCR. Unexpectedly, Nfib hemizygous mice (0/14–0%) had significantly lower mortality compared to Wt mice (10/22–45%) at 80 h of hyperoxia (P < 0.003). LD 50 was 80 h in the Wt group versus 89 h in the hemizygous group. There were no differences in BAL cell counts between the groups. Among the cytokines studied, MIP‐2 was significantly lower in hemizygous mice exposed to hyperoxia. New vessel formation, edema, congestion, and alveolar hemorrhage were noted on histopathology at 72 and 80 h in wild‐type mice. Nfib hemizygous lungs had significant downregulation of genes involved in redox signaling and inflammatory pathways. Adult Nfib hemizygous mice are relatively resistant to hyperoxia compared to wild‐type littermates. Mechanisms contributing to this resistance are not clear; however, transcription factors such as Nfib may regulate cell survival and play a role in modulating postnatal lung development.

Hyperoxia and modulation of pulmonary vascular and immune responses in COVID-19

“…In human volunteers, breathing 95% oxygen for 17 h is associated with detectable increases in alveolocapillary permeability ( 15 ). Histologically, hyperoxia drives progressive destruction of alveolocapillary membranes leading to enlargement of air spaces, alveolar hemorrhage, and vascular network remodeling ( 28 , 32 ). Regression of lung capillary network (capillary rarefaction) has been demonstrated angiographically and histologically and is a result of the destruction of alveolocapillary membranes, obstruction of capillaries by microthrombi, and vascular pruning ( 27 , 40 , 46 ).…”

“…Regression of lung capillary network (capillary rarefaction) has been demonstrated angiographically and histologically and is a result of the destruction of alveolocapillary membranes, obstruction of capillaries by microthrombi, and vascular pruning ( 27 , 40 , 46 ). The loss of the proportion of functional microcapillaries is accompanied by marked dilation and congestion of remaining vessels and diversion of blood flows (and whole cardiac output) through these remaining larger vessels, leading to pulmonary hypertension and intrapulmonary shunting ( 28 , 32 ).…”

“…The observed vascular remodeling has been attributed, at least in part, to endothelialitis, pericyte alterations, and pathological forms of intussusceptive angiogenesis (1,11). The marked vascular dilations, seen in both hyperoxia and COVID-19 microscopically (32,34) and even radiologically (39), are uncommon in other types of lung injury. It is also reasonable to posit that these pathognomonic vascular changes require extended time periods (e.g., days to weeks) to fully develop.…”

Tumor Heterogeneity Underlies Differential Cisplatin Sensitivity in Mouse Models of Small-Cell Lung Cancer

“…It has been well documented that one of the likely cells of origin of SCLC is a rare neuroendocrine (NE) cell ( Gazdar et al., 1980 , Park et al., 2011 , Sutherland et al., 2011 ). NE cells are located throughout the pulmonary tree and can be found either as single cells or in clusters called NE bodies ( Kumar et al., 2017 , Kuo and Krasnow, 2015 ). Because human SCLC is often diagnosed late in the course of the disease, computed tomography (CT) scans of SCLC patients often reveal a bulky central mass with lymph node (LN) involvement, which makes the identification of primary tumor origin difficult.…”

A de novo Non-sense Nuclear Factor I B Mutation (p.Tyr290*) Is Responsible for Brain Malformation and Lung Lobulation Defects

“…Studies on Nfib -deficient mice have shown that loss of Nfib results in perinatal lethality due to lung maturation defects along with severe callosal agenesis and forebrain defects ( 21 ). Even Nfib hemizygous mice show reduced lung maturation and decreased survival ( 22 , 23 ). Dorsal telencephalon-specific Nfib conditional knockout mice show an obvious increase in cortical size ( 12 ), which may explain the macrocephaly observed in NFIB -deficient patients.…”