HIF1α Is Essential for Normal Intrauterine Differentiation of Alveolar Epithelium and Surfactant Production in the Newborn Lung of Mice

Abstract

Neonatal respiratory distress syndrome (RDS) is mainly the result of perturbation in surfactant production and is a common complication seen in premature infants. Normal fetal lung development and alveolar cell differentiation is regulated by a network of transcription factors. Functional loss of any of these factors will alter the developmental program and impact surfactant production and normal gas exchange. During development, the fetus is exposed to varying oxygen concentrations and must be able to quickly adapt to these changes in order to survive. Hypoxia-inducible factor 1␣ (HIF1␣) is the primary transcription factor that is responsible for regulating the cellular response to changes in oxygen tension and is essential for normal development. Its role in lung maturation is not well defined and to address this knowledge gap, a lung-specific HIF1␣ knock-out model has been developed. Loss of HIF1␣ early in lung development leads to pups that die within hours of parturition, exhibiting symptoms similar to RDS. Lungs from these pups display impaired alveolar epithelial differentiation and an almost complete loss of surfactant protein expression. Ultrastructural analysis of lungs from HIF1␣ deletion pups had high levels of glycogen, aberrant septal development, and decreased expression of several factors necessary for proper lung development, including HIF2␣, ␤-catenin, and vascular endothelial growth factor. These results suggest that HIF1␣ is essential for proper lung maturation and alteration in its normal signaling during premature delivery might explain the pathophysiology of neonatal RDS.During development, an embryo is exposed to varying levels of oxygen as a balance is created between vascularization and tissue growth. Localized hypoxia, a decrease in available oxygen, is a normal part of this process. The programmed responses to these decreases in available oxygen are essential for viability (1, 2). In utero, the embryo is supplied with oxygen and nutrients through the placental barrier. Following parturition, oxygen is supplied by the neonatal lungs and therefore, proper intrauterine development of the alveolar gas exchange regions of the lung is essential for the newborn's first breath and for sustaining life outside the womb (3).Lung morphogenesis is a complex process that is orchestrated by several transcription factors, growth factors, and extracellular cues (4). For example, thyroid transcription factor-1 regulates the expression of the genes for Clara cell secretory protein (CCSP) 2 produced in Clara cells in the tracheobronchial airways and various surfactants produced by alveolar type II cells in the lung parenchyma (5, 6). CCAAT-enhancerbinding protein ␣ (CEBP␣) is essential for proper regulation of alveolar Type II cell differentiation, and Forkhead box A2 (Foxa2) controls various cellular programs involved in lung development (e.g. surfactant expression) (6 -8). Ablation of any of these factors results in major structural and functional abnormalities ranging from undeveloped alveolar structu...

Hypoxia-Inducible Factor Regulates Expression of Surfactant Protein in Alveolar Type II Cells In Vitro

“…The loss of HIF1a early in murine lung development in utero leads to pups that die within hours of birth, with symptoms similar to those of neonatal respiratory distress syndrome (16). The lungs of these pups exhibited impaired alveolar epithelial differentiation and an almost complete loss of surfactant protein expression.…”

“…In alveolar epithelial cells, HIF 1a and HIF2a are expressed, and both are regulated by hypoxia (8,(10)(11)(12)(13). HIF is also important at physiologic levels of hypoxia, for example, in tumors (where it is responsible for the Warburg effect [aerobic glycolysis]) (14), in the normal liver (15), in fetal lung (16), and in inflammatory exudates (17), as well as in severe hypoxia (1% oxygen) (12).…”

Alveolar type II cells maintain bioenergetic homeostasis in hypoxia through metabolic and molecular adaptation

“…In contrast, differentiation and development of the fetal lung distal epithelium normally occurs in low O 2 (1-5% O 2 ) (19), with hypoxia-related signaling in the pulmonary epithelium throughout gestation (8,9,28). This condition is critical for normal fetal lung development and preparation for breathing after birth (1,32). Thus, elucidating the molecular mechanisms of pulmonary adaptations to low O 2 tension is of particular clinical significance for understanding both lung pathology and normal development.…”

Hypoxia promotes thyroid differentiation of native murine induced pluripotent stem cells

“…HIFs are heterodimer complexes constituted by two subunits (Groenman et al, 2007). When exposed to low oxygen, the alpha-subunit which is easily degraded in normoxia accumulates, binds to the beta-subunit and transactivates multiple downstream genes which contain the hypoxia response elements and are involved in embryonic development (Saini et al, 2008). Our study also demonstrated that this mechanism may work in the thyroid differentiation.…”