The vitronectin-binding function of PAI-1 exacerbates lung fibrosis in mice.

Plasminogen activator inhibitor-1 (PAI-1) is increased in the lungs of patients with pulmonary fibrosis, and animal studies have shown that experimental manipulations of PAI-1 levels directly influence the extent of scarring that follows lung injury. PAI-1 has 2 known properties that could potentiate fibrosis, namely an antiprotease activity that inhibits the generation of plasmin, and a vitronectin-binding function that interferes with cell adhesion to this extracellular matrix protein. To determine the relative importance of each PAI-1 function in lung fibrogenesis, we administered mutant PAI-1 proteins that possessed either intact antiprotease or vitronectin-binding activity to bleomycin-injured mice genetically deficient in PAI-1. We found that the vitronectin-binding capacity of PAI-1 was the primary determinant required for its ability to exacerbate lung scarring induced by intratracheal bleomycin administration. The critical role of the vitronectin-binding function of PAI-1 in fibrosis was confirmed in the bleomycin model using mice genetically modified to express the mutant PAI-1 proteins. We conclude that the vitronectin-binding function of PAI-1 is necessary and sufficient in its ability to exacerbate fibrotic processes in the lung.

Macrophage-specific expression of urokinase-type plasminogen activator promotes skeletal muscle regeneration.

Macrophages (Mp) and the plasminogen system play important roles in tissue repair following injury. We hypothesized that Mp-specific expression of urokinase-type plasminogen activator (uPA) is sufficient for Mp to migrate into damaged muscle and for efficient muscle regeneration. We generated transgenic mice expressing uPA only in Mp, and we assessed the ability of these mice to repair muscle injury. Mp-only uPA expression was sufficient to induce wild-type levels of Mp accumulation, angiogenesis, and new muscle fiber formation. In mice with wild-type uPA expression, Mp-specific overexpression further increased Mp accumulation and enhanced muscle fiber regeneration. Furthermore, Mp expression of uPA regulated the level of active hepatocyte growth factor, which is required for muscle fiber regeneration, in damaged muscle. In vitro studies demonstrated that uPA promotes Mp migration through proteolytic and nonproteolytic mechanisms, including proteolytic activation of hepatocyte growth factor. In summary, Mp-derived uPA promotes muscle regeneration by inducing Mp migration, angiogenesis, and myogenesis.

HPV Immunization in High School Student-Athletes Receiving Preparticipation Physical Evaluations at Mass Event Versus Other Venues.

BACKGROUND: The preparticipation physical evaluation (PPE) is a requirement for high school sport participation in most states, but its location and role in preventive health care for adolescents is often questioned. HYPOTHESIS: Athletes who had their PPE performed in an office setting, in particular) by their primary care physician (PCP), will have higher human papillomavirus (HPV) immunization rates than those who had their PPE done in a group setting at a mass-participation PPE. STUDY DESIGN: Retrospective cohort study. LEVEL OF EVIDENCE: Level 3. METHODS: The PPE forms and immunization records for athletes at a single high school were reviewed to determine the location of PPE, the signing practitioner, and HPV immunization status. RESULTS: A total of 488 athletes (286 males, 202 females) were included; 51% had received at least 1 dose of the HPV vaccine while 39% had completed the series. There was no significant difference in vaccination rates between examination in an office setting versus a group setting. Athletes receiving their PPE at an urgent care facility had significantly lower rates of HPV series completion than all other settings (29% vs 43%; P = 0.004). PPE completion by the athlete's PCP was associated with higher rates of vaccine series completion (46% vs 34%; P = 0.014). CONCLUSION: Athletes who completed their PPE in mass event and office-based settings had similar rates of HPV vaccine series initiation and completion. PPEs done at urgent care facilities were associated with low rates of vaccine series completion, while those done by a PCP were associated with higher rates. CLINICAL RELEVANCE: HPV immunization rates in athletes are low, and the PPE represents a potential opportunity to improve immunization rates.