Hepatocyte Growth Factor

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 (4–6). 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, 8–11). 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.