Journal of Applied Physiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

J Appl Physiol 97: 1543-1548, 2004; doi:10.1152/japplphysiol.00286.2004
8750-7587/04 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (5)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yan, C.
Right arrow Articles by Du, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yan, C.
Right arrow Articles by Du, H.

INVITED REVIEW

HIGHLIGHTED TOPICS
Lung Growth and Repair

Alveolus formation: what have we learned from genetic studies?

Cong Yan1,2 and Hong Du3

1Division of Pulmonary Biology, 3Division of Human Genetics, and 2The Graduate Program for Molecular and Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, The University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039


   ABSTRACT
TOP
 ABSTRACT
ALVEOLAR FORMATION AND STRUCTURE
 PULMONARY SURFACTANT
 NUCLEAR RECEPTORS
 ALVEOLAR INJURY DURING HYPEROXIA
 GRANTS
 REFERENCES
 
The respiratory system has two basic functions: air exchange and pathogen clearance. The conducting airway and alveolar parenchyma are the basic structures to fulfill these functions during respiratory cycles. In humans, there are ~40 cell types in the lung that coordinately work together through various structural and signaling molecules. These molecules are vital for maintaining normal lung functions in response to environmental changes. Aberrant expression of these molecules can jeopardize human health and cause various pulmonary diseases. In this article, we will review some recent progress made in the pulmonary field, using genetic animal model systems to elucidate molecular mechanisms that are important for alveolar formation and lung diseases.

alveolar formation; signaling molecules; animal models


   ALVEOLAR FORMATION AND STRUCTURE
TOP
 ABSTRACT
 ALVEOLAR FORMATION AND STRUCTURE
PULMONARY SURFACTANT
 NUCLEAR RECEPTORS
 ALVEOLAR INJURY DURING HYPEROXIA
 GRANTS
 REFERENCES
 
The lung provides an interface for gas exchange between the air and blood to supply oxygen and remove carbon dioxide. Before birth, the lung develops from the foregut endoderm through the interaction between epithelial cells and mesenchymal cells. Lung epithelium undergoes multiplication of branches through embryonic [embryonic day 9 (E9)–E12 in mice], pseudoglandular (E12–E15 in mice), canalicular (E15–E17 in mice), and saccular (E17–birth in mice) stages, as demonstrated in Fig. 1.



View larger version (31K):
[in this window]
[in a new window]
  		Fig. 1. Embryonic lung development in the mouse. Lung epithelial cell marker thyroid transcription factor 1 (TTF-1) antibody was used in immunohistochemistry. E10, E12, E14, E16, E18, embryonic days 10, 12, 14, 16, and 18. Di, diverticulum; Br, bronchioli; ET, epithelial tubules. [From Naltner et al. (28).]

 
After birth, maturation of the lung continues, entering the alveolar stage. The alveolarization period starts from the late embryonic period to the neonatal period; during this period, pulmonary surfactant is secreted, primarily by nonciliated bronchiolar epithelial cells (Clara cells) and alveolar type II epithelial cells. Alveolar septation is developmentally regulated, occurring in mice from approximately postnatal days 1 through 21 and in humans during the last month of gestation and the first 8 years of life. In the mature lung, the alveolus, alveolar sac, alveolar duct, and alveolar pore form the basic alveolar structure. The interalveolar walls are supplied with capillaries, which are supported by elastic fibers and basement membranes. Their surface is covered by squamous alveolar type I epithelial cells. The round secretory alveolar type II epithelial cells are scattered around alveolar type I epithelial cells, usually in the corner of the alveoli. Alveolar type II epithelial cells contain highly distinctive granules known as lamellar bodies rich in phospholipids. When phospholipid secretory products (known as pulmonary surfactant) are released from alveolar type II epithelial cells, they spread over to form a membrane that covers the surface of the interalveolar walls. Pulmonary surfactant reduces the surface tension force at the air-water interface and facilitates expansion of alveoli. In addition to alveolar type I and II epithelial cells, alveolar macrophages with engulfed particles are also present in free alveolar air spaces and interalveolar walls.


   PULMONARY SURFACTANT
TOP
 ABSTRACT
 ALVEOLAR FORMATION AND STRUCTURE
 PULMONARY SURFACTANT
NUCLEAR RECEPTORS
 ALVEOLAR INJURY DURING HYPEROXIA
 GRANTS
 REFERENCES
 
Pulmonary surfactant is composed of structurally heterogeneous lipoproteins and is synthesized in alveolar type II epithelial cells as a vesicular structure called tubular myelin, which forms the lamellar body. After secretion from cells, pulmonary surfactant forms an insoluble film at the air-liquid interface of the alveolar surface. Around 90–95% of the pulmonary surfactant compositions are lipids. The majority of surfactant lipids are phospholipids (~80%), principally dipalmitoylphosphatidylcholine and phosphatidylglycerol. Working together with surfactant proteins, phospholipids reduce alveolar surface tension to promote lung expansion on inspiration and to prevent lung collapse on expiration.

There are ~10% neutral lipids in pulmonary surfactant. Until recently, the functional roles of neutral lipids have been poorly understood in the lung. Cholesteryl ester and triglycerides are major components in neutral lipids. Lysosomal acid lipase (LAL) hydrolyzes cholesteryl ester and triglycerides in the lysosome of cells to generate free cholesterol and free fatty acids (10, 11). Using a genetic ablation approach, researchers can reveal, via blockage of cholesteryl ester and triglyceride metabolism in LAL knockout mice (lal–/–), severe disruption of the alveolar structure, including pulmonary emphysema and remodeling (20). Associated with these phenotypes, a high level of neutrophil influx is observed in the lungs. The numbers of bronchoalveolar macrophages appear foamy and are gradually increased. Affymetrix GeneChip array analyses show increased mRNA levels of proinflammatory cytokines (including IL-1{beta}, IL-6, and TNF-{alpha}) and matrix metalloproteinases (including MMP-8, MMP-9, and MMP-12). In addition, Clara cell hypertrophy and hyperplasia are developed in conducting airways. The severity of pathophysiological phenotypes in the lal–/– mouse lungs is age dependent. It is known that many neutral lipid metabolites serve as ligands for nuclear receptors that are potent transcription factors controlling gene expression of cytokines/chemokines, proteinases, and structural proteins, which are essential for the maintenance of normal alveolar functions in various physiological conditions and host defenses. Identification of these ligands and nuclear receptors will be the major task in the pulmonary field to understand lung biology and host defenses.

In addition to lipids, pulmonary surfactant contains ~5–10% surfactant proteins, including surfactant protein A, B, C, and D (SP-A, SP-B, SP-C, and SP-D). Genetic ablations of genes encoding for these molecules have been performed in mice. Although SP-A, SP-C, and SP-D gene knockout mice are viable, they display some phenotypes similar to lal–/– knockout mice, including alveolar emphysema and inflammation-related remodeling (13–15, 17, 40). These observations suggest some common pathophysiological mechanisms between LAL and surfactant proteins. On the other hand, SP-B gene knockout mice result in lethal respiratory atelectasis after birth (6). Deficiency of SP-B did not alter embryonic lung development in this mouse model. Similar to the observation made in mice, an inherited mutation of SP-B has been identified in humans and results in lethal respiratory distress syndrome in newborn infants (29). SP-B is a 79-amino acid amphipathic peptide, produced by the proteolytic cleavage of SP-B proprotein (proSP-B) in Clara cells and alveolar type II epithelial cells. The SP-B peptide is stored in lamellar bodies and secreted with phospholipids into the airway lumen. It facilitates the stability and rapid spreading of surfactant phospholipids during respiratory cycles and is essential for maturation of alveolarization and postnatal respiratory adaptation in newborns (41).

Although SP-B deficiency has no effect on lung development, expression of the SP-B gene starts at the onset of lung formation and is developmentally controlled in a highly tissue-specific manner. The tissue- and cell-type specificities are primarily controlled by cis-acting DNA elements and trans-acting transcription factors. In a transgenic mouse model line carrying the human SP-B 1.5-kb 5'-flanking regulatory region and the lacZ reporter gene, expression of the human SP-B 1.5-kb lacZ reporter gene recapitulates the endogenous SP-B gene expression, which starts at mouse embryonic day 9 and is restricted to epithelial cells throughout lung development (Fig. 2). In lung explant cultures, the human SP-B 1.5-kb lacZ reporter gene is highly expressed in newly formed epithelial tubules during the respiratory branching process, as demonstrated in Fig. 2 (48). There are two cis-acting DNA elements highly conserved in both the human and murine SP-B 5'-flanking regulatory sequence that are essential for SP-B transcriptional activation (3, 5, 46). Deletion of the enhancer region, which binds to thyroid transcription factor 1, retinoic acid receptor (RAR), signal transducers and activators of transcription 3 (Stat3), and nuclear receptor coactivators (SRC-1, ACTR, TIF2, and CBP/p300) in the human SP-B 1.5-kb lacZ gene, abolishes lacZ reporter gene expression in Clara cells and significantly reduces its expression in alveolar type II epithelial cells in transgenic mice (48).



View larger version (54K):
[in this window]
[in a new window]
  		Fig. 2. Expression of the human surfactant protein B (hSP-B) 1.5-kb lacZ reporter gene in the mouse developing lungs. E9 and E12, embryonic days 9 and 12; P4, postnatal day 4. [From Yang et al. (48).]

 

   NUCLEAR RECEPTORS
TOP
 ABSTRACT
 ALVEOLAR FORMATION AND STRUCTURE
 PULMONARY SURFACTANT
 NUCLEAR RECEPTORS
ALVEOLAR INJURY DURING HYPEROXIA
 GRANTS
 REFERENCES
 
Gene transcriptional control is an important mechanism for alveolar maturation and maintenance. Transcription factors and coactivators regulate gene expression of structural proteins, growth factors, cytokines, chemokines, and proteinases in lung development and in adult lungs when responding to various physiological changes. For many years, hormones have been used to treat lung-associated inflammation and diseases (such as chronic obstructive pulmonary disease and asthma). Given the fact that the lung is a highly lipogenic organ, hormone activated-nuclear receptors (a unique group of transcription factors) are especially important for the formation and the maintenance of the alveolar structure. Hormonal ligands for various nuclear receptors come from lipid metabolism. Disruption of normal lipid metabolism can cause severe pulmonary inflammation and alveolar abnormality (20).

All nuclear receptors contain similar functional domains. A central DNA-binding domain is composed of two highly conserved zinc fingers and specifically binds to various hormone response elements on the target genes. A ligand-binding domain is responsible for recognition of hormones to ensure selective and specific physiological responses. An NH2-terminal transactivation domain (AF1) and a COOH-terminal ligand transactivation domain (AF2) are essential for transcriptional activation of nuclear receptors. Nuclear receptors can be monomeric, homodimeric, heterodimeric with retinoid X receptor (RXR), or both. When hormone ligands bind, nuclear receptors bind to hormone response elements and recruit nuclear receptor coactivators, including SRC-1, ACTR, TIF2, CBP/p300, p/CIP and P/CAF (5a, 16a, 16b, 36a), through the AF2 domain. These coactivators possess histone acetyltransferase (HAT) domains with intrinsic histone acetylation activity (2a, 5a, 5b, 29a, 34a). Coactivators with HATs tend to interact with each other to form a large transcription activation complex. Recruitment of multiple HATs leads to chromatin remodeling, transcription factor modification, and target gene activation (18).

The most well-characterized nuclear receptor family members in alveolarization are the RARs. RARs include three isotypes, designated {alpha}, {beta}, and {gamma}. RARs and RXRs have been previously detected in respiratory epithelial cells by immunohistochemical staining (27, 28, 44). RAR{alpha} and RAR{beta} double-null mutant mice die in utero and have severely hypoplastic lungs, suggesting that they are required for lung development (26). Retinoic acids (RAs) are the ligands for RARs. RAs are vitamin A derivatives and lipophilic hormones that can be readily diffusible through cell membranes. Early information regarding physiological functions and clinical applications of RA is derived from vitamin A-deficient animals and prenatal and postnatal infants (42, 43). Clinical studies in premature infants show a correlation between low serum levels of vitamin A and chronic lung disease after respiratory distress syndrome. Vitamin A supplementation from the early postnatal period reduces the morbidity associated with bronchopulmonary dysplasia (31–33). Importantly, treatment of animals with all-trans-RA increases the number of alveoli and reverses elastase-induced pulmonary emphysema in vivo (21, 22). It has been shown that lipid interstitial cells of the alveolar wall store retinol and are concentrated at sites of alveolus formation (9). RAs stimulate SP-B expression in respiratory epithelial cells (12, 27, 44). Delivery of all-trans RA with the use of pulmonary surface-active material to alveoli causes elevation of cellular retinol binding protein-1 mRNA in a lung-specific manner (Massaro DJ, Massaro GD, and Clerch LB, unpublished observations).

To elucidate the functional role of RARs in pulmonary alveolarization, both transgenic and knockout mouse systems have been used by several laboratories. In doxycycline-controlling double-transgenic mouse systems, the normal RA/RAR signaling pathway is interfered with overexpressing a dominant-negative RAR{alpha} (dnRAR{alpha}) in respiratory epithelial cells under the control of the human SP-C promoter or the rCCSP promoter. Overexpression of dnRAR{alpha} in neonatal lungs from day 1 to day 21 (a critical period for alveolar maturation) leads to substantial alveolar abnormality with the increased air space, larger but fewer alveoli, and diminished alveolar surface area (as demonstrated in Fig. 3). In these animals, numbers of alveolar epithelial cells are significantly reduced. Expression of the SP-B gene is inhibited in alveolar type II epithelial cells (49). This finding supports a concept that the RA/RAR axis plays a critical role in neonatal alveoli maturation. Because dnRAR{alpha} blocks RAR elements on target genes for all three forms of RARs ({alpha}, {beta}, {gamma}) in an indiscriminative fashion, it cannot address diverse and differential roles played by individual RAR isoforms in alveolarization.



View larger version (54K):
[in this window]
[in a new window]
  		Fig. 3. Disruption of the alveolar structure in the neonatal lungs of dominant-negative retinoic acid receptor-{alpha} (dnRAR{alpha}) double-transgenic mice. WT, wild-type mice; CCSP/dnRAR, doxycycline-controlled CCSP/dnRAR double-transgenic mice; SP-C/dnRAR, doxycycline-controlled SP-C/dnRAR transgenic mice. [From Yang et al. (49).]

 
To address this issue, several laboratories use genetic knockout mice to assess functional roles of each of the RAR isoforms in the lung. In 14-day-old RAR{alpha}–/– mice, the volume of individual alveoli, the number of alveoli, and alveolar surface area remain unchanged compared with wild-type mice. However, at age 50 days, the volume of individual alveoli is larger and the number of alveoli and the alveolar surface area are smaller in RAR{alpha}–/– than in wild-type mice (23). RAR{beta}–/– mice exhibit premature septation and form alveoli twice as fast as wild-type mice during the period of septation but at the same rate as wild-type mice thereafter. RAR{beta} agonist treatment of newborn animals impairs septation (24). Therefore, RAR{beta} is an endogenous inhibitor of alveolus formation during but not after the perinatal period. RAR{gamma} gene deletion results in a decrease in alveolar number and whole lung elastic tissue and an increase in cord length of alveoli at postnatal day 28. The additional deletion of RXR{alpha} allele results in a decrease in alveolar surface area and alveolar number and an increase in cord length of alveoli (25).


   ALVEOLAR INJURY DURING HYPEROXIA
TOP
 ABSTRACT
 ALVEOLAR FORMATION AND STRUCTURE
 PULMONARY SURFACTANT
 NUCLEAR RECEPTORS
 ALVEOLAR INJURY DURING HYPEROXIA
GRANTS
 REFERENCES
 
Patients with acute and chronic cardiopulmonary disorders are often given supplemental oxygen to enhance the alveolar and arterial oxygen levels. The prolonged administration of inspired oxygen at a high concentration leads to various forms of alveolar tissue damage, including acute lung injury and adult respiratory distress syndrome (7, 34). In animal models, exposure to a lethal dose of oxygen (e.g., 95%-100%) leads to acute lung inflammation and destruction of alveolar parenchyma.

Stat3 was originally identified as the acute phase response factor (1, 50). Stat3 is mainly activated by proinflammatory IL-6 family of cytokines (IL-6, IL-11, ciliary neurotrophic factor, oncostatin M, and leukemia inhibitory factor) that share the common gp130 receptor subunit (19, 36). Stat3 becomes activated by phosphorylation in response to extracellular signaling molecules (8, 35). Phosphorylation causes dimerization and translocation of Stat3 into the nucleus to activate downstream target genes. Similar to the dnRAR study, overexpression of a dominant-negative Stat3 (mutation at the phosphorylation site) in respiratory epithelial cells in doxycycline-controlled double-transgenic mice causes alveolar destruction, and animal death is increased during hyperoxia (47). Stat3C is an artificial form that mimics the phosphorylated Stat3 action with substitution of two cystine residues within the COOH-terminal loop of the SH2 domain of Stat3 (4). Overexpression of Stat3C in respiratory epithelial cells in a doxycycline-controlled double-transgenic mouse system protects lung inflammation and injury caused by hyperoxia. In this mouse line, more than 50% of transgenic mice survive to 95% oxygen exposure at day 7, compared with 0% survival of wild-type mice. Immunohistochemical study indicates that overexpression of Stat3C protects acute capillary leakage of red blood cells and neutrophil infiltration into the alveolar region (Fig. 4).



View larger version (41K):
[in this window]
[in a new window]
  		Fig. 4. Protection of hyperoxia-induced alveolar hemorrhage by overexpressing signal transducers and activators of transcription 3 (Stat3C). Arrows indicate clusters of red blood cells. Stat3C, doxycycline-treated Stat3C-overexpressing transgenic mice.

 
The extracellular matrix is the major component in the endothelial-epithelial interstitial structure along the alveolar wall. MMPs, including collagenase, gelatinase, elastase, stromelysin, and matrilysin, are zinc-dependent matrix-degrading proteinases that share structural and functional similarities. They degrade almost every component of the extracellular matrix and are required for normal lung development and remodeling after lung injury. Exuberant or aberrant expression of MMPs can cause tissue damage and has been associated with many lung diseases, including asthma, chronic obstructive pulmonary disease, cancer, and adult respiratory distress syndrome (30). Under hyperoxic conditions, neutrophil-associated MMP-9 influx to the lung is dramatically increased in wild-type animals but not in Stat3C-overexpressing double-transgenic mice. Zymographic analysis of bronchoalveolar lavage fluids shows a much higher MMP-9 enzymatic activity in oxygen-treated wild-type mice than in Stat3C-overexpressing transgenic mice (Lian X, Yang L, Xu H, Clarke A, Li T, Du H, and Yan C, unpublished observations). MMP-12 is another important proteinase that degrades elastin and type IV collagen (2, 30). After oxygen exposure, MMP-12 expression is significantly induced in the interstitial region along the alveolar wall in wild-type animals but not in Stat3C-overexpressing double-transgenic mice (Lian et al., unpublished observations). These studies support a concept that activation of the Stat3 pathway delays MMPs influx or de novo synthesis in the alveolar region to prevent alveolar wall damage and capillary leakage.

Other mechanisms may also account for Stat3 protection against oxygen-induced alveolar injury. Stat3C promotes synthesis of SP-B, which maintains the surfactant integrity. Stat3C is a potent activator for SP-B gene expression (45). Intratracheal treatment with exogenous SP-B improves survival and decreases lung injury during hyperoxia in mice (16). DNA fragmentation has also been reported in the lungs under hyperoxic condition (38). Because Stat3C is a growth-promoting molecule and prevents apoptosis, overexpression of Stat3C in respiratory epithelial cells may prevent or delay hyperoxia-induced apoptosis. Importantly, the IL-6 family of cytokines also protects against oxygen-induced lung injury (37, 39). Therefore, the IL-6 family of cytokines and the Stat3 signaling axis, which is generally regarded as a proinflammatory pathway, exhibits an anti-inflammatory function in hyperoxia-induced lung inflammation and injury.


   GRANTS
TOP
 ABSTRACT
 ALVEOLAR FORMATION AND STRUCTURE
 PULMONARY SURFACTANT
 NUCLEAR RECEPTORS
 ALVEOLAR INJURY DURING HYPEROXIA
 GRANTS
REFERENCES
 
This work was supported by National Heart, Lung, and Blood Institute Grants HL-67826 (C. Yan and H. Du) and HL-61803 (C. Yan and H. Du), March of Dimes Grant FY02–206 (C. Yan), and National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-54930 (H. Du).


   FOOTNOTES
 

Address for reprint requests and other correspondence: C. Yan, Cincinnati Children's Hospital Medical Center, Division of Pulmonary Biology, 3333 Burnet Ave., Cincinnati, OH 45229-3039 (E-mail: cong.yan{at}cchmc.org).


   REFERENCES
TOP
 ABSTRACT
 ALVEOLAR FORMATION AND STRUCTURE
 PULMONARY SURFACTANT
 NUCLEAR RECEPTORS
 ALVEOLAR INJURY DURING HYPEROXIA
 GRANTS
 REFERENCES
 

  1. Akira S, Nishio Y, Inoue M, Wang XJ, Wei S, Matsusaka T, Yoshida K, Sudo T, Naruto M, and Kishimoto T. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell 77: 63–71, 1994.[CrossRef][ISI][Medline]
  2. Banda MJ and Werb Z. Mouse macrophage elastase. Purification and characterization as a metalloproteinase. Biochem J 193: 589–605, 1981.[ISI][Medline]
  3. Bannister AJ and Kouzarides T. The CBP co-activator is a histone acetyltransferase. Nature 384: 641–643, 1996.[CrossRef][Medline]
  4. Bohinski RJ, Di Lauro R, and Whitsett JA. The lung-specific surfactant protein B gene promoter is a target for thyroid transcription factor 1 and hepatocyte nuclear factor 3, indicating common factors for organ-specific gene expression along the foregut axis. Mol Cell Biol 14: 5671–5681, 1994.[Abstract/Free Full Text]
  5. Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, and Darnell JE Jr. Stat3 as an oncogene. Cell 98: 295–303, 1999.[CrossRef][ISI][Medline]
  6. Bruno MA, Bohinski RJ, Carter JE, Foss KA, and Whitsett JA. Structure and function of the mouse surfactant protein B gene. Am J Physiol Lung Cell Mol Physiol 268: L381–L389, 1995. [Corrigenda. Am J Physiol Lung Cell Mol Physiol 268: June 1995, following table of contents.][Abstract/Free Full Text]
  7. Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, and Evans RM. Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 90: 569–580, 1997.[CrossRef][ISI][Medline]
  8. Chen H, Lin RJ, Xie W, Wilpitz D, and Evans RM. Regulation of hormone-induced histone hyperacetylation and gene activation via acetylation of an acetylase. Cell 98: 675–686, 1999.[CrossRef][ISI][Medline]
  9. Clark JC, Wert SE, Bachurski CJ, Stahlman MT, Stripp BR, Weaver TE, and Whitsett JA. Targeted disruption of the surfactant protein B gene disrupts surfactant homeostasis, causing respiratory failure in newborn mice. Proc Natl Acad Sci USA 92: 7794–7798, 1995.[Abstract/Free Full Text]
  10. Crapo JD. Morphologic changes in pulmonary oxygen toxicity. Annu Rev Physiol 48: 721–731, 1986.[CrossRef][ISI][Medline]
  11. Darnell JE Jr. STATs and gene regulation. Science 277: 1630–1635, 1997.[Abstract/Free Full Text]
  12. Dirami G, Massaro GD, Clerch LB, Ryan US, Reczek PR, and Massaro D. Lung retinol storing cells synthesize and secrete retinoic acid, an inducer of alveolus formation. Am J Physiol Lung Cell Mol Physiol 286: L249–L256, 2004.[Abstract/Free Full Text]
  13. Du H, Duanmu M, Witte D, and Grabowski GA. Targeted disruption of the mouse lysosomal acid lipase gene: long-term survival with massive cholesteryl ester and triglyceride storage. Hum Mol Genet 7: 1347–1354, 1998.[Abstract/Free Full Text]
  14. Du H, Witte DP, and Grabowski GA. Tissue and cellular specific expression of murine lysosomal acid lipase mRNA and protein. J Lipid Res 37: 937–949, 1996.[Abstract]
  15. George TN and Snyder JM. Regulation of surfactant protein gene expression by retinoic acid metabolites. Pediatr Res 41: 692–701, 1997.[ISI][Medline]
  16. Glasser SW, Burhans MS, Korfhagen TR, Na CL, Sly PD, Ross GF, Ikegami M, and Whitsett JA. Altered stability of pulmonary surfactant in SP-C-deficient mice. Proc Natl Acad Sci USA 98: 6366–6371, 2001.[Abstract/Free Full Text]
  17. Glasser SW, Detmer EA, Ikegami M, Na CL, Stahlman MT, and Whitsett JA. Pneumonitis and emphysema in sp-C gene targeted mice. J Biol Chem 278: 14291–14298, 2003.[Abstract/Free Full Text]
  18. Hawgood S, Ochs M, Jung A, Akiyama J, Allen L, Brown C, Edmondson J, Levitt S, Carlson E, Gillespie AM, Villar A, Epstein CJ, and Poulain FR. Sequential targeted deficiency of SP-A and -D leads to progressive alveolar lipoproteinosis and emphysema. Am J Physiol Lung Cell Mol Physiol 283: L1002–L1010, 2002.[Abstract/Free Full Text]
  19. Hokuto I, Ikegami M, Yoshida M, Takeda K, Akira S, Perl AK, Hull WM, Wert SE, and Whitsett JA. Stat-3 is required for pulmonary homeostasis during hyperoxia. J Clin Invest 113: 28–37, 2004.[CrossRef][ISI][Medline]
  20. Hong H, Kohli K, Trivedi A, Johnson DL, and Stallcup MR. GRIP1, a novel mouse protein that serves as a transcriptional coactivator in yeast for the hormone binding domains of steroid receptors. Proc Natl Acad Sci USA 93: 4948–4952, 1996.[Abstract/Free Full Text]
  21. Kamei Y, Xu L, Heinzel T, Torchia J, Kurokawa R, Gloss B, Lin SC, Heyman RA, Rose DW, Glass CK, and Rosenfeld MG. A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell 85: 403–414, 1996.[CrossRef][ISI][Medline]
  22. Korfhagen TR, Bruno MD, Ross GF, Huelsman KM, Ikegami M, Jobe AH, Wert SE, Stripp BR, Morris RE, Glasser SW, Bachurski CJ, Iwamoto HS, and Whitsett JA. Altered surfactant function and structure in SP-A gene targeted mice. Proc Natl Acad Sci USA 93: 9594–9599, 1996.[Abstract/Free Full Text]
  23. Kornberg RD. Eukaryotic transcriptional control. Trends Cell Biol 9: M46–M49, 1999.[CrossRef][ISI][Medline]
  24. Leonard WJ and O'Shea JJ. Jaks and STATs: biological implications. Annu Rev Immunol 16: 293–322, 1998.[CrossRef][ISI][Medline]
  25. Lian X, Yan C, Yang L, Xu Y, and Du H. Lysosomal acid lipase deficiency causes respiratory inflammation and destruction in the lung. Am J Physiol Lung Cell Mol Physiol 286: L801–L807, 2004.[Abstract/Free Full Text]
  26. Massaro GD and Massaro D. Postnatal treatment with retinoic acid increases the number of pulmonary alveoli in rats. Am J Physiol Lung Cell Mol Physiol 270: L305–L310, 1996.[Abstract/Free Full Text]
  27. Massaro GD and Massaro D. Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats. Nat Med 3: 675–677, 1997. [Corrigenda. Nat Med 3: July 1997, p. 805.][CrossRef][ISI][Medline]
  28. Massaro GD, Massaro D, and Chambon P. Retinoic acid receptor-{alpha} regulates pulmonary alveolus formation in mice after, but not during, perinatal period. Am J Physiol Lung Cell Mol Physiol 284: L431–L433, 2003.[Abstract/Free Full Text]
  29. Massaro GD, Massaro D, Chan WY, Clerch LB, Ghyselinck N, Chambon P, and Chandraratna RA. Retinoic acid receptor-{beta}: an endogenous inhibitor of the perinatal formation of pulmonary alveoli. Physiol Genomics 4: 51–57, 2000.[Abstract/Free Full Text]
  30. McGowan S, Jackson SK, Jenkins-Moore M, Dai HH, Chambon P, and Snyder JM. Mice bearing deletions of retinoic acid receptors demonstrate reduced lung elastin and alveolar numbers. Am J Respir Cell Mol Biol 23: 162–167, 2000.[Abstract/Free Full Text]
  31. Mendelsohn C, Lohnes D, Decimo D, Lufkin T, LeMeur M, Chambon P, and Mark M. Function of the retinoic acid receptors (RARs) during development. II. Multiple abnormalities at various stages of organogenesis in RAR double mutants. Development 120: 2749–2771, 1994.[Abstract]
  32. Naltner A, Ghaffari M, Whitsett JA, and Yan C. Retinoic acid stimulation of the human surfactant protein B promoter is thyroid transcription factor 1 site-dependent. J Biol Chem 275: 56–62, 2000.[Abstract/Free Full Text]
  33. Naltner A, Wert S, Whitsett JA, and Yan C. Temporal/spatial expression of nuclear receptor coactivators in the mouse lung. Am J Physiol Lung Cell Mol Physiol 279: L1066–L1074, 2000.[Abstract/Free Full Text]
  34. Nogee LM, Garnier G, Dietz HC, Singer L, Murphy AM, deMello DE, and Colten HR. A mutation in the surfactant protein B gene responsible for fatal neonatal respiratory disease in multiple kindreds. J Clin Invest 93: 1860–1863, 1994.[ISI][Medline]
  35. Ogryzko VV, Schiltz RL, Russanova V, Howard BH, and Nakatani Y. The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell 87: 953–959, 1996.[CrossRef][ISI][Medline]
  36. Shapiro SD and Senior RM. Matrix metalloproteinases. Matrix degradation and more. Am J Respir Cell Mol Biol 20: 1100–1102, 1999.[Free Full Text]
  37. Shenai JP, Chytil F, and Stahlman MT. Vitamin A status of neonates with bronchopulmonary dysplasia. Pediatr Res 19: 185–188, 1985.[ISI][Medline]
  38. Shenai JP, Kennedy KA, Chytil F, and Stahlman MT. Clinical trial of vitamin A supplementation in infants susceptible to bronchopulmonary dysplasia. J Pediatr 111: 269–277, 1987.[ISI][Medline]
  39. Shenai JP, Stahlman MT, and Chytil F. Vitamin A delivery from parenteral alimentation solution. J Pediatr 99: 661–663, 1981.[CrossRef][ISI][Medline]
  40. Smith LJ. Hyperoxic lung injury: biochemical, cellular, and morphologic characterization in the mouse. J Lab Clin Med 106: 269–278, 1985.[ISI][Medline]
  41. Spencer TE, Jenster G, Burcin MM, Allis CD, Zhou J, Mizzen CA, McKenna NJ, Onate SA, Tsai SY, Tsai MJ, and O’Malley BW. Steroid receptor coactivator-1 is a histone acetyltransferase. Nature 389: 194–198, 1997.[CrossRef][Medline]
  42. Stark GR, Kerr IM, Williams BR, Silverman RH, and Schreiber RD. How cells respond to interferons. Annu Rev Biochem 67: 227–264, 1998.[CrossRef][ISI][Medline]
  43. Taga T and Kishimoto T. Gp130 and the interleukin-6 family of cytokines. Annu Rev Immunol 15: 797–819, 1997.[CrossRef][ISI][Medline]
  44. Torchia J, Rose DW, Inostroza J, Kamei Y, Westin S, Glass CK, and Rosenfeld MG. The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function [see comments]. Nature 387: 677–684, 1997.[CrossRef][Medline]
  45. Ward NS, Waxman AB, Homer RJ, Mantell LL, Einarsson O, Du Y, and Elias JA. Interleukin-6-induced protection in hyperoxic acute lung injury. Am J Respir Cell Mol Biol 22: 535–542, 2000.[Abstract/Free Full Text]
  46. Waxman AB, Einarsson O, Seres T, Knickelbein RG, Homer R, Warshaw JB, Johnston R, and Elias JA. Targeted lung expression of interleukin-11 enhances murine tolerance of 100% oxygen and diminishes hyperoxia-induced DNA fragmentation. Chest 116: 8S–9S, 1999.[Medline]
  47. Waxman AB, Einarsson O, Seres T, Knickelbein RG, Warshaw JB, Johnston R, Homer RJ, and Elias JA. Targeted lung expression of interleukin-11 enhances murine tolerance of 100% oxygen and diminishes hyperoxia-induced DNA fragmentation. J Clin Invest 101: 1970–1982, 1998.[ISI][Medline]
  48. Wert SE, Yoshida M, LeVine AM, Ikegami M, Jones T, Ross GF, Fisher JH, Korfhagen TR, and Whitsett JA. Increased metalloproteinase activity, oxidant production, and emphysema in surfactant protein D gene-inactivated mice. Proc Natl Acad Sci USA 97: 5972–5977, 2000.[Abstract/Free Full Text]
  49. Whitsett JA, Nogee LM, Weaver TE, and Horowitz AD. Human surfactant protein B: structure, function, regulation, and genetic disease. Physiol Rev 75: 749–757, 1995.[Abstract/Free Full Text]
  50. Wolbach SB and Howe PR. Tissue changes following deprivation of fat-soluble A vitamin. J Exp Med 42: 753–777, 1925.[Abstract]
  51. Wong YC and Buck RC. An electron microscopic study of metaplasia of the rat tracheal epithelium in vitamin A deficiency. Lab Invest 24: 55–66, 1971.[ISI]
  52. Yan C, Ghaffari M, Whitsett JA, Zeng X, Sever Z, and Lin S. Retinoic acid-receptor activation of SP-B gene transcription in respiratory epithelial cells. Am J Physiol Lung Cell Mol Physiol 275: L239–L246, 1998.[Abstract/Free Full Text]
  53. Yan C, Naltner A, Martin M, Naltner M, Fangman JM, and Gurel O. Transcriptional stimulation of the surfactant protein B gene by STAT3 in respiratory epithelial cells. J Biol Chem 11: 11, 2002.[Medline]
  54. Yan C, Sever Z, and Whitsett JA. Upstream enhancer activity in the human surfactant protein B gene is mediated by thyroid transcription factor 1. J Biol Chem 270: 24852–24857, 1995.[Abstract/Free Full Text]
  55. Yang L, Lian X, Cowen A, Xu H, Du H, and Yan C. Synergy between Stat3 and RARa in regulation of the surfactant protein B gene in the lung. Mol Endocrinol 18: 1520–1532, 2004.[Abstract/Free Full Text]
  56. Yang L, Naltner A, Kreiner A, Yan D, Cowen A, Du H, and Yan C. An enhancer region determines hSP-B gene expression in bronchiolar and ATII epithelial cells in transgenic mice. Am J Physiol Lung Cell Mol Physiol 284: L481–L488, 2003.[Abstract/Free Full Text]
  57. Yang L, Naltner A, and Yan C. Overexpression of dominant negative retinoic acid receptor alpha causes alveolar abnormality in transgenic neonatal lungs. Endocrinology 144: 3004–3011, 2003.[Abstract/Free Full Text]
  58. Zhong Z, Wen Z, and Darnell JE Jr. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264: 95–98, 1994.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Proc Am Thorac SocHome page
A. Sharafkhaneh, N. A. Hanania, and V. Kim
Pathogenesis of Emphysema: From the Bench to the Bedside
Proceedings of the ATS, May 1, 2008; 5(4): 475 - 477.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
K. C. Wade, S. H. Guttentag, L. W. Gonzales, K. L. Maschhoff, J. Gonzales, V. Kolla, S. Singhal, and P. L. Ballard
Gene Induction during Differentiation of Human Pulmonary Type II Cells In Vitro
Am. J. Respir. Cell Mol. Biol., June 1, 2006; 34(6): 727 - 737.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
X. Lian, C. Yan, Y. Qin, L. Knox, T. Li, and H. Du
Neutral Lipids and Peroxisome Proliferator-Activated Receptor-{gamma} Control Pulmonary Gene Expression and Inflammation-Triggered Pathogenesis in Lysosomal Acid Lipase Knockout Mice
Am. J. Pathol., September 1, 2005; 167(3): 813 - 821.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (5)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yan, C.
Right arrow Articles by Du, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yan, C.
Right arrow Articles by Du, H.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2004 by the American Physiological Society.