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Departments of Medicine, Pediatrics, Neurobiology, Pharmacology, and Physiology, and Anesthesiology and Critical Care; and the Committees on Molecular Medicine, Cell Physiology, and Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, Illinois
Correspondence and requests for reprints should be addressed to Alan R. Leff, M.D., Department of Medicine, MC 6076, The University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637. E-mail: aleff{at}medicine.bsd.uchicago.edu
Nearly all drugs used for treatment of airway disease are homologs or close derivates of the sympathomimetics, parasympatholytics, cromones, and methylxanthines that were developed more than 50 years ago. By the standards of classical reversible airflow obstruction (e.g., asthma), the application of these derivatives to the treatment of chronic obstructive pulmonary disease (COPD) has been marginally successful in reversing airflow obstruction and relieving symptoms. The reason for this is the nature of the anatomic changes in COPD. Bronchodilation is a poor target for treatment of COPD if the goal is to restore patients with advanced disease to near-normal lung function.
This conference was convened to examine the possibilities for the distant future (20 years or more)—possibilities that will lead to the restoration of normal lung structure in lungs that are severely damaged from COPD. The conference was entitled "Tissue Remodeling and Repair in COPD." By repair, the conferees were examining the hypothesis that an understanding of the process by which lung development occurs could be harnessed to redevelop new, normal lung units where terminal damage had already occurred. Much of the conference focused on alveolation, and, hence, on classically defined emphysema only. COPD is nonetheless an airway and alveolar disease, and it is not clear that the same processes would apply for repair of conducting airways and alveoli.
As summarized by David Warburton, lung development starts at 5 weeks, at which time a tracheal evagination from the esophagus can be visualized. The conducting portion of the airway extends to branch ultimately into alveolated tissue. The conducting airways at each branch point are sacrificed for the next generation so that the 300 million alveoli from which we exchange gas are formed from a single ancestral bud. Airway branching is mostly complete at birth, but the development of alveolation continues to age 8 years. Several important points emerged from this discussion. First, airways in the fetus and young infant develop in an optimal environment over a normal substrate that is not damaged by disease. Second, timing is everything. The brilliant choreography of lung branching and morphogenesis is precisely timed. Specific genes have been identified, but generating new lung from proximal airways requires timely promotion and termination of gene expression. The developmental priority lies in the stem cell hierarchy. Improper expression of the FgF-10 gene can lead to massive overalveolation. Vascular endothelial growth factor, which controls vascular morphogenesis when overexpressed in mice, leads to devastating hypervascularity. Specific mutations that affect elastin expression can create an emphysema-like phenotype. Excessive expression of tumor growth factor (TGF)-ß is particularly enigmatic. Overexpression of TGF-ß causes bronchopulmonary dysplasia in neonatal mice and fibrosis in adults. However, TGF-ß is essential in lung development. In the SMAD-3 knockout mouse, transforming growth factor (TGF)-ß produces insufficient alveolation, which is not the case in the SMAD-3 wild-type mice.
In morphogenesis, each alveolus needs a stem cell to direct further development, a critical point of later discussion of stem-cell therapies. A further consideration raised in early discussion during the conference was that smokers vary in their susceptibility to develop COPD. Clearly, there is a genetic determination of susceptibility to injury caused by cigarette smoke. Children with bronchopulmonary dysplasia show some tendency to improve by remodeling. It remains unclear whether the capacity for regenerative remodeling (re-remodeling) in a mouse, which develops its lungs in 21 days, applies to humans, who require 8 years for complete lung development. As alveolar proliferation stops at age 8, does this end our capacity to regenerate as well?
Further developmental considerations in lung regeneration were noted by Rubin Tudor, who indicated that heterogeneity of the lung resulting from cigarette-induced lung injury may be adaptive. Although heterogeneity between ventilation and perfusion causes poor arterial oxygenation, emphysema involves alveoli and capillaries; hence, emphysema does not necessarily alter blood oxygenation. Heterogeneous multifocal centrilobular emphysema is a less advanced state than homogenous panacinar disease. In Tudor's view, emphysema is a process of protease–antiprotease interactions with apoptosis of alveolar cell and oxidative stress. Oxidative stress causes centralobular emphysema, as does blockade of the vascular endothelial growth factor receptor, whereas a panacinar pattern develops from lack of 
1-antiprotease.
Subsequent discussions by Nick Morrell examined models of pulmonary hypertension, an eventual consequence of advanced COPD. Understanding has advanced from genetic studies of primary pulmonary hypertension (PPH), which in its familial form is dominantly expressed but has only a 30% penetrance. Seventy percent of families with PPH have exaggerated TGF-ß activity. Increased TGF-ß signaling results from impaired bone morphogenetic protein receptor signaling via SMAD 1/5; this causes an impaired antiproliferative effect on pulmonary vascular smooth muscle. These data point to the importance of genetics in targeting defects in major components of COPD, but it was acknowledged that PPH may not model the secondary hypertension of COPD.
A particularly innovative challenge to the conventional representation of the pathogenesis of emphysema was suggested by Norbert Voelkel, who proposed that the inflammation of emphysema results from an autoimmune process. Emphysema in this conception was viewed as the result of increased apoptosis of endothelial (rather than epithelial) cells. Voelkel posited that components of dying cells are processed as immunogenetic peptides. Arguments in favor of this view focus on the fact that emphysema occurs only in a minority of smokers; hence, there has to be some genetic proclivity for the disease. Voelkel pointed to the work of Peter Wagner, who has shown apoptosis in skeletal muscle of patients with emphysema. Voelkel also suggested that an autoimmune process might account for the persistent inflammation observed in emphysema in some patients even after smoking cessation and the presence of lymphoid hyperplasia, lymphocytes, and mast cells in the lungs of patients with emphysema. Thus, the signal is from the outside-in and the response from inside-out. Voelkel acknowledged the absence of an identifiable circulating antibody and the apparent lack of efficacy of corticosteroids in ameliorating the process of remodeling in COPD. This view was regarded by the group as challenging and subject to considerable interpretation, comparable to that of the masterful work of art provided by Professor Voelkel for the cover of this issue of PATS.
Tim Higenbottam returned the conference to the real world of therapeutics by outlining goals for the future. A central issue was identified as using the vasculature of the lung to aid in its own repair. Are lungs capable of repair in smokers who develop emphysema? Is tissue-specific repair from stem cells possible?
These and other issues were discussed categorically as follows. Diane Krause presented data to suggest that bone marrow elements may become epithelial stem cells in the lung. Unfortunately, there remain significant questions. It is not clear whether these are true epithelial stem cells or fusion cells derived from bone marrow stem cells. Engraftment to the lung seems to be only 0.1%, although physiologically significant function of cystic fibrosis transmembrane conductance regulator activity can be detected as different from control. The process also requires considerable radiation injury to allow engraftment. This is an area of huge promise and substantial challenge. It will nonetheless likely be an essential component of any therapy for lung regeneration—keeping in mind David Warburton's explanation that every new alveolus requires a stem for development.
Jack Gauldie implicated TGF-ß as the most important molecule in connective tissue remodeling and fibrosis. SMAD-3 signaling activated by TGF-ß is, however, involved in pulmonary fibrosis and in emphysema. Hence, the events regulating chronic scarring and fibrosis in the lung are a balance between inflammation and repair. Working from the outside-in, in contrast to Norbert Voelkel's hypothesis, denudation of epithelium rather than endothelium initiates early fibrosis with collagen, laminin, and fibronectin deposition. This may progress to chronic scarring or emphysema. In mouse models, TGF-ß is detectable only for 2 weeks during the remodeling process and then is down-regulated. The mechanism by which progression absent TGF-ß continues requires further definition. TGF-ß–initiated fibrosis is blocked in the SMAD-3 knockout mouse. However, at 3–4 months, SMAD-3 knockout mice develop emphysema. These models exemplify changes in the microenvironment that may occur within the same lung. In humans, one part of the lung may develop cystic lesions while another zone develops fibrosis. Such is the case in usual interstitial pneumonitis in humans. These data point to the regional microenvironment of the lung as created by the extracellular matrix as the final determinant of lung remodeling. These points again raised concern in discussion of how difficult it will be to regulate regeneration and preserve the homogeneous development of a normal regenerated area.
Steve Rennard emphasized that the reparative process requires the cessation of the processes causing continuation of lung injury. At a minimum, this requires smoking cessation; however, 20% of patients with COPD are nonsmokers. Hence, the continued injury imposed by continued smoking, the continued inflammation that persists even after cessation of smoking, and the ability to develop COPD without smoking suggest a much more complex picture than direct injury caused persistently by cigarette smoke. Reversing the process of injury and tissue destruction requires smoking cessation, but regeneration requires more than mere cessation of toxin exposure. Emphysema is accelerated by poor nutritional status, which affects the balance between repair and injury. Cell–cell interactions determine the heterogeneous microenvironments in which injury and repair occur. For example, smoke can inhibit the action of low concentrations of TGF-ß, but at greater concentrations, smoke can convert the latent form to active TGF-ß. Hence, the resulting tissue damage can depend on the local microenvironment. Dr. Lee presented some animal models from the laboratory of Jack Elias, demonstrating in rodent species that Th1 and Th2 responses are likely involved in lung injury of emphysema, lending credence to the conceptual notion of the Dutch hypothesis in the development of COPD. His TGF-ß transgenic mice demonstrated that apoptotic cells are critical for the induction of fibrosis and alveolar changes of emphysema.
These discussions were expanded by Peter Henson, who indicated that apoptosis in COPD originates from the interaction between the macrophage and engulfment of lung epithelial cells. The induction of apoptosis in causing COPD, however, is not solely caused by cigarette smoke but also by poor clearance of apoptotic cells. One may regard the process as a net loss of epithelial cells from the alveolar walls. In time, the wall itself is lost—the vanishing lung.
Scott Randell pointed out that COPD is not just emphysema, but rather a diffuse involvement of the entire bronchopulmonary tree. Nearly all patients with COPD have loss of alveoli and fibrotic narrowing of the terminal conducting airways of the lung. The processes mediating the injuries to diverse regions of the lung occur in differing microenvironments. Successful treatment of the alveolar microenvironment, which is the zone affected in emphysema, does not address the therapeutic regenerative needs of most patients with COPD, who have diffuse involvement of airways and alveoli. Randell also related interesting data on the regenerative potential of the damaged airway, suggesting that a pleuripotential cell is capable of regenerating into the variety of cells that normally populate the airway. Among these are the mucus-producing cells. Edith Puchelle examined in detail the role of injury caused by metalloproteinases and their inhibitors, which lead to marked remodeling of the airway epithelium. The shift from serous cells to mucous cells and ciliated epithelium to squamous cells demonstrates the considerable plasticity of the conducting airway and gas exchange airways of the lung. Understanding the biologically active molecules discussed in this presentation and throughout the conference is the basis for the development of lung regenerative therapies.
Some additional points were emphasized on several occasions during the discussion.
ACKNOWLEDGMENTS
The author thanks Prof. Stephen Rennard for critical review of these summarizing comments. Opinions expressed here do not necessarily reflect those of conference participants or Prof. Rennard.
FOOTNOTES
Conflict of Interest Statement: A.R.L. received a $2,500 honorarium for attending this conference. He has no other financial relationship with the sponsor, AstraZeneca.
(Received in original form June 12, 2006; accepted in final form June 12, 2006)
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