A review of the alpha-1 foundation: its formation, impact, and critical success factors.

Patient-advocacy organizations have proliferated because they can be an effective method to advance research and clinical care for those with the index condition, and can produce substantial benefits for the affected community, especially when the condition is uncommon. To clarify critical success factors in organizing a patient-advocacy organization and to provide a blueprint for others, including the respiratory-care advocacy community, this report examines features of one highly successful organization, the Alpha-1 Foundation, which is committed to helping those with the genetic condition alpha-1 antitrypsin deficiency. Features of the Alpha-1 Foundation that underlie its success include: consistently creating partnerships with key stakeholders, including the scientific and clinical communities, government, and pharmaceutical manufacturers; bringing passion to the cause (eg, by assuring that organizational leadership is provided by individuals affected by alpha-1 antitrypsin deficiency); and developing strategic business partnerships, as with a company that administers alpha-1 antitrypsin treatment (so-called intravenous augmentation therapy) and employs individuals with alpha-1 antitrypsin deficiency. Funds allocated by the company help to underwrite the foundation's research-funding commitment. The foundation also recruits and retains talent, including alpha-1 patients, to leadership roles (eg, on the board of directors) and has a voluntary group of committed scientists and clinicians. We believe that attention to these factors can help assure the success of patient-advocacy groups.

Induction of the myofibroblast phenotype following elastolytic injury to mouse lung.

The repair of alveolar structures following endotracheal administration of porcine pancreatic elastase (PPE) to mice involves the coordinated deposition of new matrix elements. We determined the induction of the myofibroblast phenotype following elastolytic injury to mouse lung by examining the expression of alpha-smooth muscle actin (alpha-SMA) by immunohistochemistry. We also examined elastin and alpha1(I) collagen mRNA expression by in situ hybridization. Changes in airspace dimensions were assessed by determining mean linear intercept. In untreated mice, alpha-SMA was localized to vascular structures and large airways, with no detectable expression in alveolar units. PPE induced alpha-SMA expression in damaged areas surrounding large vessels, in septal remnants, and in the opening ring of alveolar ducts. Elastin and alpha1(I) collagen mRNA expression were up-regulated in residual alveolar structures and septal walls. PPE dose-response studies indicated that alpha1(I) collagen and elastin mRNA expression were not induced in areas of normal lung adjacent to damaged lung. The administration of low dose PPE resulted in increased alpha-SMA protein and elastin mRNA expression in the cells comprising the opening ring of alveolar ducts. Our data suggest that repair mechanisms following elastolytic injury are confined to overtly damaged alveolar structures and involve the induction of the myofibroblast phenotype.

Veterans Administration support for medical research: opinions of the endangered species of physician-scientists.

Over the past three decades the Veterans Affairs (VA) Research program has evolved into a powerful, peer-reviewed funding mechanism for basic and translational research that has resulted in numerous important contributions to medical science and improvements in patient care. Continuity in VA Merit Review funding has fostered and nurtured the scientific careers of a large number of physician-scientists who have remained devoted to the mission of performing creative and innovative research that affects the patient care mission of the VA. VA medical research policies have undergone a major overhaul in the past year. Although many of these changes (de-emphasizing bench research and revamping the peer review process) have recently been reversed, the future direction of VA research remains in flux. The goal of this manuscript is to demonstrate the importance of the Merit Review medical research funding mechanism not just to the VA, but to the entire nation's health care system. To achieve this goal, the opinions of 65 established VA medical investigators were obtained regarding the past success and future direction of VA research. The conclusions reached include the following. 1) Merit Review research funding has been essential to the training, recruitment, and retention of productive VA physician-scientists. 2) The VA research program has contributed both basic and clinical innovations that have led to improvements in medical care. Contributions of VA researchers to excellence in many aspects of patient care at VA hospitals have been extraordinary. 3) Development of initiatives that entice outstanding Ph.D.'s to develop their careers in the VA has been crucial to the success of the program. 4) The VA research program has fostered a mutually beneficial relationship with affiliated medical schools. 5) Better methods to quantify VA research contributions and outcomes are essential for future program development.

Retinoic acid does not affect alveolar septation in adult FVB mice with elastase-induced emphysema.

BACKGROUND: Administration of ALL-TRANS retinoic acid (ATRA) to adult Sprague-Dawley rats with emphysema induced by porcine pancreatic elastase (PPE) reversed the emphysema perhaps by inducing new alveolar formation. OBJECTIVE: A study was conducted to determine whether ATRA can induce new alveolar septa and reverse the airspace enlargement caused in adult mice by PPE treatment. METHODS: 48 FVB mice were divided into 6 groups. Three groups received 15 microg of PPE in 0.1 ml of 0.9% saline and 3 groups received 0.1 ml of saline, intratracheally. Starting at day 22, the mice received 12 daily intraperitoneal injections of cottonseed oil, with or without ATRA (12.5 microg or 50 microg). The mice were killed for study 1 day after the last injection. RESULTS: Measurements of plasma and lung tissue ATRA levels showed statistically significant elevated levels after the 50-microg but not after the 12.5-microg doses of ATRA. In situ hybridization studies of elastin and alpha(1)(I) collagen mRNA expression in pulmonary parenchyma as well as in airways and blood vessels showed no effect of ATRA. Airspace size was determined by the mean linear intercept (Lm) method. The Lm of the groups receiving PPE and ATRA (46.2 +/- 4.1 microm, mean +/- SD) was not significantly different from the group receiving PPE and oil (47.8 +/- 6.0 microm). The Lm for groups receiving saline and ATRA (40.6 +/- 2.5 microm) were not significantly different from the group receiving saline and oil (41.0 +/- 2.7 microm). Comparison of the fixed lung volume data and calculated internal surface area also showed no differences between the control and ATRA-treated groups. CONCLUSION: ATRA treatment does not affect airspace size or expression of elastin or alpha(1)(I) collagen mRNA in adult FVB mice with PPE-induced emphysema.

Enhancement of exercise performance in COPD patients by hyperoxia: a call for research.

This essay summarizes 16 reports, published since 1956, that describe the effects of hyperoxia on exercise endurance in persons with COPD who have severe airflow obstruction (ie, FEV(1) < 1.0 L or < 39% of predicted) and mild hypoxemia at rest (ie, PaO(2) > 62 mm Hg or arterial oxygen saturation [SaO(2)] measured by pulse oximetry of > 91%). The term hyperoxia is used because, in a proportion of study participants, oxygen administration increased exercise endurance in a dose-dependent fashion, up to a fraction of inspired oxygen of 0.5 or a flow of 100% O(2) of 6 L/min. The process appears to be dependent on an increase in PaO(2) rather than on the restoration of SaO(2) to normal levels. The results of pulmonary function tests were not predictive of response. Increased exercise performance was associated with a decrease in dyspnea, respiratory frequency, and minute ventilation. The slowing of respiratory frequency and the decrease in pulmonary air trapping likely accounted for the decrease in dyspnea. Slowing of the respiratory rate, which occurred at the expense of the retention of CO(2), is most likely due to a hyperoxia-induced decrease in chemoreceptor ventilatory drive from the aortic and carotid bodies. Research is called for to determine the following: (1) the prevalence of COPD patients who have severe airflow limitation accompanied by mild hypoxemia; (2) the proportion of these patients who show improvements in exercise performance during a test of hyperoxic exercise; and (3) whether enhanced exercise performance during a brief test translates into a meaningful increase in the ability to perform the activities of daily living.

Severity of elastase-induced emphysema is decreased in tumor necrosis factor-alpha and interleukin-1beta receptor-deficient mice.

A single intratracheal dose of porcine pancreatic elastase, which is cleared from the lung by 24 hours, was administered to wild-type, IL-1beta type 1 receptor-deficient, double TNF-alpha (type 1 and type 2) receptor-deficient, and combined TNF-alpha (type 1 receptor) plus IL-1beta receptor-deficient mice. The mean linear intercept (Lm) of saline-treated mice was 32(3) microm [mean(SE)]. For wild-type elastase-treated mice, Lm was 81(6) microm at 21 days versus 52(5) microm at 5 days after treatment, indicating that alveolar wall remodeling occurs long after the elastase injury. At 21 days, Lm values were 67(10), 62(3), and 39(5) microm in elastase-treated mice deficient in the IL-1beta receptor, double TNF-alpha receptors, and combined receptors, respectively. The level of apoptosis assessed by a terminal deoxynucleotidyl transferase-catalyzed in situ nick end-labeling assay was increased at 5 days after elastase treatment and was markedly and similarly attenuated in the IL-1beta, the double TNF-alpha, and the combined receptor-deficient mice. Our results indicate that inflammatory mediators exacerbate elastase-induced emphysema. We estimate that in the combined TNF-alpha + IL-1beta receptor-deficient mice, inflammation accounts for about 80% of the emphysema that develops after elastase treatment; decreased apoptosis of lung cells likely contributes to decreased severity of emphysema.