The role of thrombin and protease activated receptor-1 in the pathogenesis of pulmonary fibrosis.

Pulmonary fibrosis is characterised by excessive deposition of extracellular matrix proteins within the lung parenchyma. Activation of the coagulation cascade occurs in this condition and thrombin levels are increased in bronchoalveolar lavage fluid (BALF) from patients with this disorder. In addition to its role in blood coagulation, thrombin exerts cellular effects, including promoting fibroblast proliferation, procollagen production and expression of connective tissue growth factor (CTGF) via activation of protease activated receptor-1 (PAR-1). This thesis examined the hypothesis that thrombin plays a role in promoting lung collagen accumulation in pulmonary fibrosis, via activation of PAR-1. To address this hypothesis, the effect of a direct thrombin inhibitor, UK-156406 on bleomycin-induced pulmonary fibrosis was examined in rats. In addition, the effect of bleomycin-induced pulmonary fibrosis in PAR-1 knockout (PAR-1-/-) and wild-type (WT) mice was evaluated. In rats, immunohistochemical expression of thrombin and PAR-1 were dramatically increased in the lung following bleomycin instillation, compared with saline-treated animals. Following bleomycin instillation, lung collagen doubled and was preceded by significant elevations in 1(I) procollagen and CTGF mRNA levels. In bleomycin-treated animals receiving an anticoagulant dose of UK-156046, lung collagen accumulation, 1(I) procollagen and CTGF mRNA levels were all significantly reduced. In WT mice given bleomycin, total lung collagen was increased but in bleomycin-instilled PAR-1-/- mice, lung collagen accumulation was significantly reduced biochemically and histologically. Furthermore, BALF total inflammatory cell number, total protein and CTGF mRNA levels were also significantly reduced in bleomycin-instilled PAR-1-/- mice compared with WT mice receiving bleomycin. In summary, this thesis shows that direct thrombin inhibition attenuates lung collagen accumulation in bleomycin-induced pulmonary fibrosis and also that PAR-1-/- mice are protected from bleomycin-induced lung injury. These data support the hypothesis that thrombin and PAR-1 play a critical role in experimental pulmonary fibrosis and that the pro-fibrotic effects of thrombin in this model, may be mediated, at least in part, via a CTGF-dependent mechanism

Models of peer support to remediate post-intensive care syndrome: A report developed by the SCCM Thrive International Peer Support Collaborative

Objective: Patients and caregivers can experience a range of physical, psychological, and cognitive problems following critical care discharge. The use of peer support has been proposed as an innovative support mechanism. Design: We sought to identify technical, safety and procedural aspects of existing operational models of peer support, among the Society of Critical Care Medicine Thrive Peer Support Collaborative. We also sought to categorize key distinctions between these models and elucidate barriers and facilitators to implementation. Subjects: 17 Thrive sites from the USA, UK, and Australia were represented by a range of healthcare professionals. Interventions: Via an iterative process of in-person and email/conference calls, members of the Collaborative, defined the key areas on which peer support models could be defined and compared; collected detailed self-reports from all sites; reviewed the information and identified clusters of models. Barriers and challenges to implementation of peer support models were also documented. Results: Within the Thrive Collaborative, six general models of peer support were identified: Community based, Psychologist-led outpatient, Models based within ICU follow-up clinics, Online, Groups based within ICU and Peer mentor models. The most common barriers to implementation were: recruitment to groups, personnel input and training: sustainability and funding, risk management and measuring success. Conclusion: A number of different models of peer support are currently being developed to help patients and families recover and grow in the post-critical care setting