Regulation of Alveolar Procoagulant Activity and Permeability in Direct Acute Lung Injury by Lung Epithelial Tissue Factor

Tissue factor (TF) initiates the extrinsic coagulation cascade in response to tissue injury, leading to local fibrin deposition. Low levels of TF in mice are associated with increased severity of acute lung injury (ALI) after intratracheal LPS administration. However, the cellular sources of the TF required for protection from LPS-induced ALI remain unknown. In the current study, transgenic mice with cell-specific deletions of TF in the lung epithelium or myeloid cells were treated with intratracheal LPS to determine the cellular sources of TF important in direct ALI. Cell-specific deletion of TF in the lung epithelium reduced total lung TF expression to 39% of wild-type (WT) levels at baseline and to 29% of WT levels after intratracheal LPS. In contrast, there was no reduction of TF with myeloid cell TF deletion. Mice lacking myeloid cell TF did not differ from WT mice in coagulation, inflammation, permeability, or hemorrhage. However, mice lacking lung epithelial TF had increased tissue injury, impaired activation of coagulation in the airspace, disrupted alveolar permeability, and increased alveolar hemorrhage after intratracheal LPS. Deletion of epithelial TF did not affect alveolar permeability in an indirect model of ALI caused by systemic LPS infusion. These studies demonstrate that the lung epithelium is the primary source of TF in the lung, contributing 60–70% of total lung TF, and that lung epithelial, but not myeloid, TF may be protective in direct ALI

Regulation of Alveolar Procoagulant Activity and Permeability in Direct Acute Lung Injury by Lung Epithelial Tissue Factor

Tissue factor (TF) initiates the extrinsic coagulation cascade in response to tissue injury, leading to local fibrin deposition. Low levels of TF in mice are associated with increased severity of acute lung injury (ALI) after intratracheal LPS administration. However, the cellular sources of the TF required for protection from LPS-induced ALI remain unknown. In the current study, transgenic mice with cell-specific deletions of TF in the lung epithelium or myeloid cells were treated with intratracheal LPS to determine the cellular sources of TF important in direct ALI. Cell-specific deletion of TF in the lung epithelium reduced total lung TF expression to 39% of wild-type (WT) levels at baseline and to 29% of WT levels after intratracheal LPS. In contrast, there was no reduction of TF with myeloid cell TF deletion. Mice lacking myeloid cell TF did not differ from WT mice in coagulation, inflammation, permeability, or hemorrhage. However, mice lacking lung epithelial TF had increased tissue injury, impaired activation of coagulation in the airspace, disrupted alveolar permeability, and increased alveolar hemorrhage after intratracheal LPS. Deletion of epithelial TF did not affect alveolar permeability in an indirect model of ALI caused by systemic LPS infusion. These studies demonstrate that the lung epithelium is the primary source of TF in the lung, contributing 60–70% of total lung TF, and that lung epithelial, but not myeloid, TF may be protective in direct ALI

Spinal Pathologies in Fossil Hominins

Back disorders are often conjectured to be a trade-off to the evolution of upright bipedalism. Yet, this association has not been substantiated so far. This chapter presents an overview of the known spinal pathologies in the hominin fossil record. Apart from a benign primary bone tumour in MH1 (Australopithecus sediba) and developmental defects in the Middle Pleistocene Pelvis 1 individual from Sima de los Huesos, the Kebara 2 Neanderthal and two individuals from El Sidrón, they include pathologies related to the biomechanical failure of the growing spine and degenerative osteoarthritis. While the latter is particularly common in Neanderthals, biomechanical failure of the growing spine seems to have affected all hominin species. This includes spondylolisthesis in the Pelvis 1 individual from Sima de los Huesos, traumatic juvenile disc herniation in KNM-WT 15000 (Homo erectus), anterior disc herniation (limbus vertebra) in StW 431 (A. africanus), and Scheuermann’s disease in A.L. 288-1 (A. afarensis) and three isolated thoracic vertebrae from Hadar, Sts 14 (A. africanus), SKX 3342 (Paranthropus robustus), the Pelvis 1 individual from Sima de los Huesos and perhaps Kebara 2 and Shanidar 3. Juvenile disc herniation, traumatic anterior disc herniation and Scheuermann’s disease all involve displacement of disc material and have a higher incidence following strains and trauma to the spine during the increased vulnerability phase of the pubertal growth spurt. The remarkably high prevalence of this kind of disorders in our ancestors might suggest that our spine has become less vulnerable during the course of human evolution