Lymphotoxin-␣ (LT␣), IntroductionRecent years have seen great advances in the molecular understanding of lymphatic vessels and lymphangiogenesis. 1 Studies with genetically engineered mice identified several key growth factors, transcription factors, transmembrane glycoproteins, and signaling proteins that are crucial for lymphatic vessel development and function. [2][3][4][5] Varying deficiencies in these critical molecules resulted in a spectrum of lymphedema phenotypes ranging from edematous embryos with chylous ascites and severe vascular defects associated with perinatal lethality, 3,6 to more subtle manifestations of lymphatic function defects. [7][8][9] Derangements in the structure or function of lymphatic vessels may induce edema. 1 Chy mice, in which a heterozygous mutation in the Vegfr3 gene results in inactivation of vascular endothelial growth factor 3 (VEGFR-3) signaling, exhibit lymphedema only in the fore and hind paws despite an absence of lymphatics in the entire dermis, thus demonstrating the effectiveness of compensatory mechanisms. 9 Lymphangiogenesis has been shown to occur at the sites of inflammation in models of corneal transplantation and airway infection. [10][11][12] During chronic inflammation in autoimmunity, graft rejection and infection, chronic accumulations of lymphoid cells that resemble lymph nodes, termed "tertiary lymphoid organs" (TLOs) develop, many of which require members of the lymphotoxin (LT)/TNF family. 13 Lymphangiogenesis has been described in TLOs in thyroiditis, sialitis, rheumatoid arthritis, and chronic kidney graft rejection. [14][15][16][17] LTs, key mediators of inflammation through the induction of chemokines and vascular adhesion molecules, 18 also play crucial roles in lymphoid organ development. 19 The homotrimer LT␣ 3 is secreted by CD4 ϩ Th1, CD8 ϩ , NK, B, and lymphoid tissue inducer cells and signals through TNFR1 and TNFR2, explaining its partial redundancy to TNF␣ 3 , which signals through the same receptors. 20 TNF␣ is made by a wider variety of cells, including macrophages, in addition to the LT␣-producing lymphocytes. The LT␣ monomer also forms a heterotrimer with LT␤ that is required for the cell surface expression of the LT␣␤ complex. 21 The LT␣ 1 ␤ 2 complex binds to and signals through the LT␤R. Mice deficient in LT␣ lack all lymph nodes and Peyer patches, 19 whereas those deficient in LT␤ retain some cervical, sacral, and mesenteric lymph nodes. 22 Transgenic expression of mouse LT␣ under the control of the rat insulin promoter II (RIP) leads to its expression in the ␤ cells of the islets of Langerhans in the pancreas as expected, and in the skin 23 and proximal convoluted tubules of the kidney 23,24 as this promoter is somewhat "leaky." These mice develop accumulations of T and B cells, dendritic cells, follicular dendritic cells, and macrophages that are organized into TLOs that resemble lymph nodes in cellular composition and compartmentalization, the presence of high endothelial venules (HEVs) and lymphoid chemokine expression, 18,25 du...

Evaluation of rectal and rectosigmoid sensation is important in basic, clinical and pharmacological studies. New methods to evoke and assess multimodal (electrical, thermal and mechanical) experimental pain of the upper gut activate distinct pathways and mimics clinical pain. The aims of the current study were to characterize the sensory response and reproducibility to multimodal stimulation of rectum and the rectosigmoid. A multimodal rectal probe was developed. Mucosal electrostimulation was delivered at the recto-sigmoid junction. In Rectum, impedance planimetry was used for measurement of cross-sectional area (CSA) during distension. Circulation of water within the bag at either 4 or 60 degrees C was applied for thermal stimulation. The method was tested in 12 healthy volunteers (six men mean age 32 years) on two subsequent days. Mechanical and sensory responses and referred pain areas were assessed. Stimulation with electrical, thermal and mechanical modalities resulted in different sensory perceptions. The relationship between stimulus intensity and sensory response was linear for all modalities. Sensory response to different modalities did not differ between investigation days (all P-values > 0.1). Approximately 75% of subjects felt referred pain in distinct skin locations. Between-days reproducibility was good for all modalities [intra-class correlation (ICC) > or = 0.6]. At sensory threshold, CSA showed best reproducibility (ICC > or = 0.9). At pain detection threshold stretch ratio, CSA and electrostimulation showed best reproducibility (ICC = 1.0; 0.9; 0.9). The present model was easily implemented, robust and showed good reproducibility. It can be used to study pathophysiology or pharmacological interventions in healthy controls and in patients with diseases involving the distal hindgut.

Despite extended experience with ECC rewarming, improved handling strategies, and intensive care, no overall improvement in survival was observed. Good outcome was observed even among patients with a dismal prognosis.

Objective-Collagen-binding integrins may be involved in controlling interstitial fluid pressure (Pif), transcapillary fluid flux, and tissue fluid volume. Our aim was to explore whether the newly discovered collagen binding ␣11␤1 integrin has a mechanistic role in inflammatory edema formation. Methods and Results-In collagen matrices seeded with a mixture of mast cells and fibroblasts, fibroblasts lacking the ␣11 integrin subunit (␣11 Ϫ/Ϫ ) contracted collagen gels less efficiently than control fibroblasts, suggesting that the ␣11␤1 integrin is able to mediate tensile force in connective tissues. In ␣11 Ϫ/Ϫ mice, control Pif in skin did not differ from the pressure found in wild-type mice. Whereas a reduction in Pif was found in control mice after inducing inflammation, thereby contributing to fluid extravasation and edema formation, such a reduction was not seen in ␣11 Ϫ/Ϫ mice. That this effect is mediated through the extracellular compartment is suggested by a similar plasma protein extravasation ratio in ␣11Ϫ/Ϫ and wild-type mice. Conclusions-Our data suggest that ␣11␤1 integrins on dermal fibroblasts mediate collagen lattice remodeling and have a mechanistic role in controlling Pif in inflammation and thereby fluid extravasation and edema formation in vivo. Key Words: collagen Ⅲ endothelium Ⅲ extracellular matrix Ⅲ genetically altered mice Ⅲ microcirculation F luid flux across the capillaries is governed by hydrostatic and colloid osmotic pressure gradients between plasma and interstitium. Edema (ie, extravascular fluid accumulation in the tissue) is one of the key features of inflammation and is the result of increased transcapillary fluid transport in this condition. During inflammation there is an increased capillary leakage, but also initially a rapid decrease in the hydrostatic pressure outside the capillary, the interstitial fluid pressure (Pif), which is quantitatively more important than increased capillary permeability as a driving force in the initial phase of edema generation. 1,2 Traditionally, cells are not included in the interstitium, defined as the extracellular compartment between the blood vessels and lymphatics of a tissue. 3,4 In recent studies, however, we have shown an active role of the interstitium in edema generation during inflammation (reviewed in 2 ), and in the present context we include cells (ie, fibroblasts) when addressing the mechanisms for edema generation. Furthermore, our studies have suggested a role for integrins in controlling interstitial fluid volume (Vif) by their ability to modulate force from the cytoskeleton inside the cells to the structural proteins (ie, collagens) of the extracellular matrix outside the cell. The normal fluid homeostasis is dependent on functioning collagen-binding integrins, and the result of perturbed integrin function can be edema. 2,5,6 There are four collagen-binding integrins: ␣1␤1, ␣2␤1, ␣10␤1 and ␣11␤1, and in previous studies we have shown a role for ␣2␤1 in control of Vif. 6,7 The ␣11␤1 integrin has, similar to the ␣2␤1 integr...