IntroductionMigration inhibitory factor (MIF) is a pleotropic cytokine which plays a pivotal role in inflammatory and immune-mediated diseases such as rheumatoid arthritis (RA) and atherosclerosis. MIF is secreted by T lymphocytes and macrophages on lipopolysaccharide (LPS) exposure and induces secretion of tumor necrosis factor-␣ (TNF-␣) by mouse macrophages. 1,2 In RA, MIF is highly expressed in macrophages, endothelial cells, synovial tissue (ST) fibroblasts, serum, and synovial fluids. 1,2 MIF stimulates macrophage release of proinflammatory cytokines such as TNF-␣, interleukin 1 ␤ (IL-1␤), 4 MIF up-regulates IL-1␤, matrix metalloproteinases (MMPs) MMP-1, MMP-3, MMP-9, and MMP-13 in RA ST fibroblasts. 5,6 In rodent arthritis models, administration of anti-MIF antibody ameliorates arthritis with profound inhibition of clinical and histologic features of disease. [7][8][9] Anti-MIF treatment ameliorates acute encephalomyelitis and experimental autoimmune myocarditis in mice. 10,11 These studies show a key role of MIF in the pathogenesis of immunologic and inflammatory diseases.We have shown that MIF is a potent angiogenic factor. 12 Anti-MIF inhibits tumor growth and tumor-associated angiogenesis, and MIF is a required factor for tumor-initiated endothelial cell proliferation and tumor neovascularization. 13,14 Vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in soluble forms (sVCAM-1 and sICAM-1, respectively) are potent angiogenic mediators, and RA synovial fluid-induced angiogenesis is blocked by anti-VCAM-1. 15,16 MIF is found in human vascular endothelial cells, which have been considered to play a pivotal role in systemic inflammatory and immunologic diseases by producing cytokines and growth factors. 17 Adhesion of inflammatory cells to vascular endothelium is the initial step in leukocyte recruitment and is mediated by a number of cell adhesion molecules such as ICAM-1, VCAM-1, E-, P-, and L-selectin, as well as integrins. MIF up-regulates ICAM-1 on endothelial cells. 18 Rat kidney VCAM-1 and ICAM-1 expression are decreased by anti-MIF treatment, blocking the development of glomerulonephritis. 19 Similarly, anti-MIF prevents VCAM-1 up-regulation on endothelial cells and improves acute encephalomyelitis in mice. 11 Cell adhesion molecules mediate and amplify the inflammatory response by allowing the ingress of leukocytes into diseased tissues. 20-22 VCAM-1 and ICAM-1 may be used as a reliable measure of the extent of atherosclerotic progression, and focal expression of adhesion molecules is consistently found in atherosclerotic plaques in humans. [22][23][24] The most compelling data for the necessity of adhesion molecules in the development of atherosclerotic plaques came from a report indicating that mice deficient in adhesion molecules are protected against atherosclerosis when fed an atherogenic diet. 25 Those studies support the role of adhesion molecules in immune-mediated diseases. For personal use only. on May 11, 2018. by guest www.bloodjournal.org From ...

Background: Disruption of fibrinolytic homeostasis participates in the pathogenesis of severe lung diseases like acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF) and plastic bronchitis. We have developed a pulmonary formulation of tissue plasminogen activator (pftPA) that withstands nebulization and reaches the lower airways.

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