Is There More to Lung Development Than Steroids and Surfactant? – Statistical Data Included
ABBREVIATIONS. PAP, pulmonary alveolar proteinosis; GMCSF, granulocyte-macrophage colony-stimulating factor; CAM, cystic adenomatoid malformation; Shh, Sonic hedgehog; ptc, patched; PDGF-A, platelet-derived growth factor A.
There has been a recent renaissance in the field of lung development. More has been learned about how the lungs are formed and how they grow in the last 10 years than in all the prior years combined. Striking parallels have emerged between mouse models and actual human diseases and developmental defects. The following is a brief review of our current understanding of the regulating factors and their interactions.
One of the most interesting of the recent insights into pulmonary molecular physiology occurred by pure serendipity. Pulmonary alveolar proteinosis (PAP) is an extraordinary disease in which the lungs are filled with a proteinaceous, lipid-rich material. Little was known about the cause. Then oncologist Glenn Dranoff and colleagues, attempting to identify molecules that could be useful in enhancing tumor vaccines, created a knockout mouse of granulocyte-macrophage colony-stimulating factor (GMCgF). Surprisingly, the mice had no abnormalities of immunity, but they were born with lungs that resembled those of human patients with PAP. Indeed, it appears that GM-CSF regulates the clearance of surfactant from the lung by macrophages. Some patients with PAP actually have a defect in the GM-CSF receptor. Fortunately, these new insights have allowed for novel therapeutic interventions including recombinant GM-CSF and possibly in the future, bone marrow transplantation to replace abnormal lung macrophages.
In contrast to the research on PAP, other lines of investigation have depended less on serendipity and more on a targeted approach to identify the earliest progenitors of the embryonic lung. The lung bud grows toward mesenchyme and subdivides in an orderly process known as branching morphogenesis. Growth factors regulate this process. They are secreted by the developing epithelium to act on the mesenchyme and visa versa. Some of these factors are expressed in a clump of cells around the budding trachea and they specify where the tracheal buds should grow. Growth factors act on receptors to initiate a signaling cascade that leads to the activation of proteins (transcription factors) that upregulate the genes that control development.
The profile of growth factors changes at defined points during development. A number of important growth factors were first identified in the fruit fly, which has a primitive respiratory system. Despite the differences when compared with the vertebrate respiratory system, the mechanisms involved in the regulation of respiratory system development in the fruit fly have illuminated our understanding of vertebrate lung development. One fly growth factor is named branchless because tracheal buds failed to grow when it was mutated. The branchless growth factor is remarkably similar to mammalian FGF10 and FGF7, which seem to fulfill very similar functions in the mouse. Deletion of FGF10 or its receptor leads to abnormal bronchial development. On the other hand, overexpression of FGF7 causes excess development of premature bronchi and results in a condition similar to a human lung malformation called cystic adenomatoid malformation (CAM). There are concerns that CAM is a premalignant condition and this mouse model produced by excess growth factor adds to this concern.
Connective tissue and cartilage surround the proximal airway. This tissue is derived from the mesenchyme. As lung development proceeds and respiratory bronchioles are formed, the connective tissue lining becomes reduced thus facilitating gas exchange between air in the alveolus and blood in the surrounding capillaries. A factor called Sonic hedgehog (Shh) is secreted by the epithelium and acts on a receptor in the mesenchyme, called patched (pfc) which in turn activates transcription factors called Glil, 2, and 3. This cascade maintains the mesenchymal coat. As lung development proceeds this pathway is down regulated. Mice with a knockout of Shh have developmental defects of the foregut including tracheoesophageal fistulas. Interestingly, human mutations of Shh are associated with holoprosencephaly. This condition has been associated with foregut anomalies in some patients, suggesting that Shh is also active in the development of the human foregut.
The most distal ends of the developing respiratory tree form gas-exchange regions of the lung that includes the respiratory bronchioles, the alveolar ducts, and the alveoli. Alveologenesis occurs in 2 distinct stages. A sac forms in the wall of the alveolar duct and is further divided by septa into alveoli resulting in a dramatic increase in the surface area for gas exchange. The myofibroblasts play a critical role in septa formation by secreting elastin and collagen. The myofibroblast number and secretory ability are regulated by platelet-derived growth factor-A (PDGF-A), which is secreted by the alveolar epithelium to act on the PDGF-A receptor on the myofibroblast. When the PDGF-A gene is deleted in mice, septation does not occur and the mice develop emphysema. On the other hand in fibrotic lung disease, there are excess myofibroblasts and, consequently, increased deposition of collagen. Retinoic acid, the active metabolite of vitamin A, also regulates septation and alveolar formation. Retinoic acid has been used to promote alveologenesis in rat models of emphysema. New therapies are being designed to treat emphysema based on our new understanding of molecular factors that regulate development. These therapies combined with the use of giucocorticoids may be useful in treating the very premature lung.
Finally, the identification of the earliest cells committed to form the lung may help to isolate the airway and parenchymal stem cells, if they exist. The purification and growth of these cells in vitro would be an enormous boon to research in pulmonology. These cells could be used for in vitro drug testing, as targets for gene therapy vectors, and as the progenitor cells for tissue replacement therapies. Given the lack of effective therapies for many pulmonary diseases and the obvious problems with lung transplantation on a large scale, it is likely that research into lung organogenesis will provide valuable insights into human pulmonary disease and therapeutics.
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Jayaraj Rajagopal, MD([double dagger]), and T. Bernard Kinane, MD(*)([sections])
From the (*)Pediatric Pulmonary Unit and the ([double dagger])Pulmonary and Critical Care Unit, ([sections])Departments of Medicine and Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Received for publication Mar 10, 2000; accepted Mar 10, 2000. Address correspondence to T. Bernard Kinane, MD, Pediatric Pulmonary Unit, Vincent Burham Basement, 55 Fruit St, Massachusetts General Hospital, Boston, MA 02114. E-mail: firstname.lastname@example.org PEDIATRICS (ISSN 0031 4005). Copyright [C] 2000 by the American Academy of Pediatrics.
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