PERSPECTIVES
Hepatocyte Growth Factor
The Key to Alveolar Septation?

Robert J. Mason

Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado

	Introduction

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The means to stimulate alveolar septation in the adult lung is the holy grail of emphysema research. Most alveolar septation occurs postnatally, especially in the newborn period (1, 2). However, it can occur later in life, albeit at a slower rate. The molecular control of septation is a relatively unexplored challenge for pulmonary biologists. Without a doubt, this is a very complex process that involves formation of alveolar walls with geometric patterning, new epithelium, endothelium, extracellular matrix, and other components of the alveolar wall. However, these events occur, must be regulated, and can be stimulated by compensatory growth after pneumonectomy. It is my contention that the factors that regulate compensatory growth will be similar to those that regulate alveolar septation in the newborn and will lead to new treatments for emphysema. I also believe that those factors which regulate alveolar septation will be different from those that regulate branching morphogenesis in the fetal lung. However, others have suggested that genes related to early branching morphogenesis such as wnt, homeobox, and hedgehog genes will also be important in compensatory growth (3). Time will tell.

Compensatory growth has been studied extensively in the liver (4). It is well known that, if 70% of a rat liver is removed surgically, the liver will grow back to its original mass in two weeks. The rate and completeness of this process is dependent on the mass of liver removed, the age of the animal, cytokines, growth factors, nutritional elements, and activation of certain stem cells (4, 5). Although many individual growth factors have been implicated in liver regeneration, it is still not well understood in terms of the initiating signaling, the growth factors involved, or the complex patterning that is required to link up the sinusoids, the biliary system, and the portal and systemic circulations.

Compensatory growth also follows pneumonectomy (7). Clinically, it is often stated that the remaining lung will grow to the original size in children up to the end of adolescence. Older individuals, who have lungs removed for lung cancer, have a much more limited response. After pneumonectomy in young animals, remarkable changes occur to increase lung mass, lung volume, and area for gas diffusion (8, 9). Most experts conclude that new alveolar septation occurs (3, 8). Alveolar septation is usually measured indirectly as alveolar surface area, number of alveoli, or septal mass. Factors that regulate compensatory lung growth include amount of lung removed, age of the animal, mechanical stimulation, growth factors, retinoids, and glucocorticoids (3, 8). Factors that do not seem to be important are the increased relative blood flow due to the removal of one lung or hypoxia (3, 8). Sakamaki and coworkers in this issue suggest that the prime growth factor responsible for this response is hepatocyte growth factor (HGF) (12). This conclusion is based on the temporal expression of the HGF mRNA in the lung, HGF levels in serum, inhibition of growth by neutralizing antibodies to HGF, and acceleration of the response by exogenous HGF.

	HGF as a Mitogen and Morphogen

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HGF is a multifunctional heparin-binding growth factor that is a mitogen for epithelial and microvascular endothelial cells, a motogen that causes epithelial cells to lose focal adhesions and scatter, and a morphogen that stimulates the formation of tubular structures of certain epithelial cells (For reviews see Refs. 13-15) (Figure 1). The protein was independently isolated as HGF, a factor produced by fibroblasts that stimulates epithelial cell proliferation, and as scatter factor, a protein that stimulates MDCK cells to dissociate and migrate (16). Of note, in the original report, the mRNA for HGF is expressed at very high levels in the lung compared with other organs (17). As shown in Figure 2, the protein is synthesized as a large single-strand protein of 728 amino acids, secreted, and then proteolytically cleaved to form a 69-kD  and a 34-kD  chain heterodimer joined by a single disulfide bridge (19, 20). The  unit contains an N-terminal hairpin loop and four kringle domains, which is analogous to the structure of plasminogen. The first two kringle loops are critical for binding to the c-Met/HGF receptor. The  unit is structurally homologous to the catalytic domain of serine proteases, but has no protease activity because of two mutations. HGF is synthesized by a variety of cell types, including fibroblasts, macrophages, and other hematopoietic cell types, smooth muscle cells, and epithelial cells. In fibroblasts, HGF expression can be stimulated by interleukin (IL)-1 and tumor necrosis factor (TNF)-, but not IL-6 or interferon (IFN)-, and is inhibited by transforming growth factor (TGF)- (21). Following a variety of injuries, circulating levels of HGF increase and the circulating HGF may come from newly synthesized pools as well as from stored intracellular pools or HGF bound to extracellular matrix. HGF, like IL-1, also has naturally-occurring competitive antagonists, which may be clinically important (22). The extracellular processing appears to occur in the organ that is injured (25). Proteolytic activation has been demonstrated by urokinase and tissue plasminogen activators and martriptase, an epithelial surface serine protease (19, 20). The receptor for HGF is cMet, a receptor tyrosine kinase. cMet is a heterodimeric protein, whose  subunit has an intracellular tyrosine kinase domain and is expressed on most epithelial cells, including malignant epithelial cells and microvascular endothelial cells. Multiple signaling pathways are induced by HGF interaction with its cognate receptor, and these have recently been reviewed (14, 26- 28). Gene targeting of HGF or cMet is fetal lethal with impairment of placental and hepatic growth (29).

View larger version (23K): [in this window] [in a new window]   Figure 1.   HGF has pleotropic effects. HGF can be an endocrine, a paracrine, or an autocrine growth factor for epithelial cells and can have effects other than simple growth. All of these effects can be envisioned to be important in alveolar septation and compensatory lung growth.

View larger version (21K): [in this window] [in a new window]   Figure 2.   Processing of HGF. HGF is synthesized as a single chain pre pro HGF, secreted as an inactive pro HGF, and then proteolytically processed to become active HGF at sites of injury. This drawing was modified from others in the literature (13, 14).

	HGF in Compensatory Growth

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Sakamaki and coworkers suggest that a prime growth factor responsible for compensatory growth in the lung is HGF (12). HGF has also been implicated in compensatory growth in the liver and the kidney (13, 30, 31). In addition, some of the HGF that increases in serum after partial hepatectomy or nephrectomy comes from the lung (32). Although the levels rise in serum and in tissue, there are concerns that it is not proteolytically activated in the responding organs (33). This issue was not addressed in the report by Sakamaki and colleagues. HGF stimulates the proliferation of alveolar and bronchial epithelial cells as well as microvascular endothelial cells (34).

	HGF in Lung Injury

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HGF has also been implicated as an important mitogen in the repair process after lung injury. Serum and lavage levels increase after a variety of lung injuries (32, 41). HGF is also increased in edema fluid from patients with acute respiratory distress syndrome compared with those with cardiogenic pulmonary edema (42). In idiopathic pulmonary fibrosis, HGF protein is readily identified in macrophages and hyperplastic type II cells, whereas it is not detected in type II cells in normal lung (43). Most importantly, recombinant HGF can be used to treat several lung injuries. HGF will reduce bleomycin induced lung injury, when it is given after the insult (44, 45). Similar results have been reported for renal or hepatic injuries (46). HGF can also prevent or reverse renal toxicity of cis platinum (50). It may be that HGF could reverse drug-induced pulmonary diseases. One minor issue is that HGF, as opposed to keratinocyte growth factor (KGF), likely impairs surfactant production by type II cells, and, hence, KGF may not be the panacea for all facets of lung injury (51). The possibility that HGF accelerates the migration of epithelial cells to close wounds of the epithelium after injury is intriguing but not clearly established in vivo. Nevertheless, HGF deserves more attention in acute lung injuries and as a potential therapeutic agent.

	Research Questions to be Resolved

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Specificity

The article by Sakamaki and associates identifies the participation of HGF in compensatory lung growth, but fails to examine the specificity of the response. For example, both epidermal growth factor (EGF) and insulin-like growth factor (IGF) have been directly implicated in other studies (52). Because the mRNA analyses were done by real-time PCR with specific primers and probes, it would not have been difficult to measure the mRNA levels at least for these growth factors, KGF, TGF-, and heparin-binding EGF and their receptors. It is highly likely that there would have been alterations in several other growth factors. However, establishing their importance at the protein level would be significantly more difficult, and this is presumably why these additional studies were not done. Future studies can be done with gene-targeted mice that lack a specific growth factor or its receptor, but there is always the caveat of compensatory mechanisms and the likelihood of redundancy in the system. It is highly likely that multiple growth factors will be involved in compensatory lung growth.

Physiologic Growth

Although Sakamaki and colleagues provide data on an increase in lung weight with treatment with recombinant HGF, there are no physiologic data to demonstrate an increase in lung volume or morphologic data to indicate an increase in alveolar septation or an increase in surface area for gas exchange. Further studies are required to complete the quantitation of the HGF response and to compare the magnitude of the HGF response to those reported previously for EGF, IGF-1, and retinoids (52).

Left versus Right Pneumonectomy

The most common experimental approach is the left pneumonectomy in rats and mice, which is relatively easy surgically and very reproducible. This is the approach that was used in the article by Sakamari and coworkers. However, left pneumonectomy only removes ~ 45% of the lung mass. Based on the studies of hepatectomy, it is likely that the magnitude of the response will be more limited than with the more challenging right pneumonectomy. This indicates that the events that regulate compensatory growth might be more evident with the right pneumonectomy model. This is clearly true in dogs (55), but it may not be so apparent in rats and mice, which continue to grow throughout their adult life.

Alveolar Septation in the Adult

Alveolar septation in the adult remains the major challenge. Gloria and Don Massaro have pioneered the studies of alveolar septation in rodents (56). They have demonstrated that retinoids increase septation in newborn rat lung and in the adult rat lung after protease instillation, which produces an emphysema-like alveolar wall destruction. Corticosteroids decrease septation. Retinoids have also been reported to stimulate lung growth after pneumonectomy (54). Alveolar septation can be studied during compensatory lung growth following pneumonectomy, in the newborn period as it occurs naturally, or in the repair process following the instillation of proteases such as elastase or papain. What is not known is whether HGF can stimulate these latter two processes. HGF, KGF (fibroblast growth factor [FGF]-7), and FGF-10 are all intriguing growth factors, because they stimulate the proliferation of alveolar epithelial cells and microvascular endothelial cells and do not stimulate fibroblast growth. However, the most subtle and perhaps challenging issue is the determination of the site for septal initiation. The ability to stimulate alveolar septation and growth will not happen soon, but it is not impossible and deserves to be a goal for the research community.

	Footnotes

Address correspondence to: Robert J. Mason, M.D., Department of Medicine, National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80110. E-mail: masonb{at}njc.org

(Received in original form March 22, 2002).

Acknowledgments: Supported in part by grants from the National Institutes of Health (HL-29891 and HL-67671).

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