In the inflamed cornea, there is a parallel outgrowth of blood and lymphatic vessels into the normally avascular cornea. We tested whether adaptive and/or innate immune cells were actively involved in the genesis of new lymphatic vessels. Our results indicate that innate immune cells (CD11b + macrophages, but not CD11c + dendritic cells) physically contributed to lymphangiogenesis under pathological conditions and that bone marrow-derived CD11b + macrophages expressed lymphatic endothelial markers such as LYVE-1 and Prox-1 under inflamed conditions in the corneal stromata of mice. Furthermore, blood vascular endothelial cells that expressed the Tie2 promoter did not contribute to newly formed lymphatic vessels under inflamed conditions. Our in vitro experiments demonstrated that CD11b + macrophages alone were capable of forming tube-like structures that expressed markers of lymphatic endothelium such as LYVE-1 and podoplanin. The novel finding that CD11b + macrophages are critical for the development of inflammation-dependent lymphangiogenesis in the eye suggests a new mechanism of lymphangiogenesis.
Impaired wound healing is a common complication of diabetes. Although it is well known that both macrophages and blood vessels are critical to wound repair, the role of wound-associated lymphatic vessels has not been well investigated. We report that both the presence of activated macrophages and the formation of lymphatic vessels are rate-limiting to the healing of diabetic wounds. We have previously shown that macrophages contribute to the lymphatic vessels that form during the acute phase of corneal wound healing. We now demonstrate that this is a general phenomenon; cells that co-stain for the macrophage marker F4/80 and the lymphatic markers LYVE-1 (lymphatic vascular endothelium hyaluronate receptor) and podoplanin contribute to lymphatic vessels in full-thickness wounds. LYVE-1-positive lymphatic vessels and CD31-positive blood vessels were significantly reduced in corneal wound healing in diabetic mice (db/db) (P < 0.02) compared with control (db/؉) mice. Glucose treatment of control macrophages led to the down-regulation of the lymphaticspecific receptor VEGFR3 and its ligands, vascular endothelial growth factor-C and -D (VEGF-C, -D). Interleukin-1 stimulation rescued diabetic macrophage function; application of interleukin-1-treated db/db-derived macrophages to wounds in db/db mice induced lymphatic vessel formation and accelerated wound healing. These observations suggest a potential therapeutic approach for healing wounds in diabetic patients.
The creep deformation resistance and rupture life of high Cr ferritic steel with a tempered martensitic lath structure are critically reviewed on the basis of experimental data. Special attention is directed to the following three subjects: creep mechanism of the ferritic steel, its alloy design for further strengthening, and loss of its creep rupture strength after long-term use.The high Cr ferritic steel is characterized by its fine subgrain structure with a high density of free dislocations within the subgrains. The dislocation substructure is the most densely distributed obstacle to dislocation motion in the steel. Its recovery controls creep rate and rupture life at elevated temperatures. Improvement of creep strength of the steel requires a fine subgrain structure with a high density of free dislocations. A sufficient number of pinning particles (MX particles in subgrain interior and M 23 C 6 particles on sub-boundaries) are necessary to cancel a large driving force for recovery due to the high dislocation density. Coarsening and agglomeration of the pinning particles have to be delayed by an appropriate alloy design of the steel.Creep rupture strength of the high Cr ferritic steel decreases quickly after long-term use. A significant improvement of creep rupture strength can be achieved if we can prevent the loss of rupture strength. In the steel tempered at high temperature, enhanced recovery of the subgrain structure along grain boundaries is the cause of the premature failure and the consequent loss of rupture strength. However, the scenario is not always applicable. Further studies are needed to solve this important problem of high Cr ferritic steel. MX particles are necessary to retain a fine subgrain structure and to achieve the excellent creep strength of the high Cr ferritic steel. Strengthening mechanism of the MX particles is another important problem left unsolved.KEY WORDS: steel for elevated temperature service; creep; strengthening mechanism; alloy design; microstructure; microstructural degradation.
There is concurrent, VEGF-A-dependent hem- and lymphangiogenesis after normal-risk keratoplasty within the preoperatively avascular recipient bed. Inhibition of hem- and lymphangiogenesis (afferent and efferent arm of an immune response) after normal-risk corneal transplantation improves long-term graft survival, establishing early postoperative hem- and lymphangiogenesis as novel risk factors for graft rejection even in low-risk eyes.
After a temporary inflammatory insult to the cornea, there is initially parallel outgrowth of both blood and lymphatic vessels. But thereafter, lymphatic vessels regress earlier than blood vessels and are completely regressed by 6 months. Earlier regression of pathologic corneal lymph versus blood vessels suggests that corneal graft survival in high-risk eyes might best be delayed for a prolonged interval following an inflammatory insult.
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