168
H. A. Marquez and F. Chen
et al. 2007), but whether or how RA interacts with these signals in this process has
not been studied.
RA also appears to be critical for the patterning of the developing cartilaginous
rings of the airways, which provides structural support for lumen patency and muscle
attachment in the trachea and major bronchi. Genetic inactivation of RARγ or deletion
of both RARα and β2 in mice results in malformation of the cartilaginous ring and
upper airway collapse in 100% of embryos, similar to the phenotype seen in type 1
tracheomalacia in humans (Carden et al. 2005; Lohnes et al. 1993; Luo et al. 1996).
This defect is specific to the large airways, since deletion of RA receptors does not
affect the development of cartilaginous tissue in other organ systems.
The diaphragm is the primary inspiratory muscle and forms a barrier between
the chest and abdominal cavities. A defect in the diaphragm results in herniation
of abdominal content into the thorax. CDH, often associated with ipsilateral lung
hypoplasia and pulmonary hypertension (PH), occurs in approximately one in 300
births and is associated with high neonatal mortality and morbidity (Gaxiola et al.
2009; Torfs et al. 1992). Whether the lung phenotypes associated with CDH occur
independently or are due to herniated abdominal content is debated. CDH is observed
in VAD rat embryos (Wilson et al. 1953), RAR antagonist-treated mouse embryos
(Clugston et al. 2010), and Rarα/β 2 compound double-null mutants (Mendelsohn
et al. 1994). Diaphragmatic defects are also seen in rat embryos treated with the
herbicide nitrofen and other teratogens that interfere with RA synthesis and activity
in vivo. The incidence and severity of the diaphragmatic defect induced by nitrofen
can be partially rescued by vitamin A or RA in rodents (Babiuk et al. 2004; Thebaud
et al. 1999). In humans, markers of vitamin A status, such as the plasma levels of
vitamin A, are lower in some newborn infants with CDH as compared with healthy
neonates (Major et al. 1998). Furthermore, studies of chromosomal abnormalities
associated with CDH have identified multiple candidate genes related to the RA
pathway (Goumy et al. 2010). Thus, RA signaling is likely required for diaphragm
development. Interestingly, CDH-associated PH, characterized by extensive muscularization of the vessels, may also be due to RA deficiency, as prenatal administration
of RA in the nitrofen-induced rat model of CDH attenuates arterial wall thickness,
improves oxygenation, and reduces pressure in the pulmonary artery (Burgos et al.
2018).
During the pseudoglandular and canalicular stages of lung development, ASM
differentiation takes place in the mesenchyme adjacent to the airways in a region
of high RA activity (Chen et al. 2014). Endogenous RA blocks excessive ASM formation by depressing the smooth muscle differentiation program when airways are
branching. A brief period of dietary VAD or inhibition of RAR-mediated signaling during development results in an aberrant ASM phenotype with increased and
ectopic expression of smooth muscle markers, such as Acta2 (alpha-actin-2), Tagln
(transgelin), and Myh11 (myosin heavy chain 11) (Chen et al. 2014) (Fig. 6.6). The
aberrant ASM phenotype induced by embryonic VAD has a long-lasting functional
effect in the postnatal lung.
H. A. Marquez and F. Chen
et al. 2007), but whether or how RA interacts with these signals in this process has
not been studied.
RA also appears to be critical for the patterning of the developing cartilaginous
rings of the airways, which provides structural support for lumen patency and muscle
attachment in the trachea and major bronchi. Genetic inactivation of RARγ or deletion
of both RARα and β2 in mice results in malformation of the cartilaginous ring and
upper airway collapse in 100% of embryos, similar to the phenotype seen in type 1
tracheomalacia in humans (Carden et al. 2005; Lohnes et al. 1993; Luo et al. 1996).
This defect is specific to the large airways, since deletion of RA receptors does not
affect the development of cartilaginous tissue in other organ systems.
The diaphragm is the primary inspiratory muscle and forms a barrier between
the chest and abdominal cavities. A defect in the diaphragm results in herniation
of abdominal content into the thorax. CDH, often associated with ipsilateral lung
hypoplasia and pulmonary hypertension (PH), occurs in approximately one in 300
births and is associated with high neonatal mortality and morbidity (Gaxiola et al.
2009; Torfs et al. 1992). Whether the lung phenotypes associated with CDH occur
independently or are due to herniated abdominal content is debated. CDH is observed
in VAD rat embryos (Wilson et al. 1953), RAR antagonist-treated mouse embryos
(Clugston et al. 2010), and Rarα/β 2 compound double-null mutants (Mendelsohn
et al. 1994). Diaphragmatic defects are also seen in rat embryos treated with the
herbicide nitrofen and other teratogens that interfere with RA synthesis and activity
in vivo. The incidence and severity of the diaphragmatic defect induced by nitrofen
can be partially rescued by vitamin A or RA in rodents (Babiuk et al. 2004; Thebaud
et al. 1999). In humans, markers of vitamin A status, such as the plasma levels of
vitamin A, are lower in some newborn infants with CDH as compared with healthy
neonates (Major et al. 1998). Furthermore, studies of chromosomal abnormalities
associated with CDH have identified multiple candidate genes related to the RA
pathway (Goumy et al. 2010). Thus, RA signaling is likely required for diaphragm
development. Interestingly, CDH-associated PH, characterized by extensive muscularization of the vessels, may also be due to RA deficiency, as prenatal administration
of RA in the nitrofen-induced rat model of CDH attenuates arterial wall thickness,
improves oxygenation, and reduces pressure in the pulmonary artery (Burgos et al.
2018).
During the pseudoglandular and canalicular stages of lung development, ASM
differentiation takes place in the mesenchyme adjacent to the airways in a region
of high RA activity (Chen et al. 2014). Endogenous RA blocks excessive ASM formation by depressing the smooth muscle differentiation program when airways are
branching. A brief period of dietary VAD or inhibition of RAR-mediated signaling during development results in an aberrant ASM phenotype with increased and
ectopic expression of smooth muscle markers, such as Acta2 (alpha-actin-2), Tagln
(transgelin), and Myh11 (myosin heavy chain 11) (Chen et al. 2014) (Fig. 6.6). The
aberrant ASM phenotype induced by embryonic VAD has a long-lasting functional
effect in the postnatal lung.