AJP - Heart Email Content Delivery
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 295: H555-H560, 2008. First published June 13, 2008; doi:10.1152/ajpheart.00161.2008
0363-6135/08 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
295/2/H555    most recent
00161.2008v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Svendsen, O. S.
Right arrow Articles by Reed, R. K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Svendsen, O. S.
Right arrow Articles by Reed, R. K.

Integrin {alpha}vβ3 acts downstream of insulin in normalization of interstitial fluid pressure in sepsis and in cell-mediated collagen gel contraction

Øyvind Sverre Svendsen,1,3,* Åsa Lidén,1,* Torbjørn Nedrebø,1,3 Kristofer Rubin,2 and Rolf K. Reed1

1Department of Biomedicine, University of Bergen, Bergen, Norway; 2Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden; and 3Department of Anesthesia and Intensive Care, Haukeland University Hospital, Bergen, Norway

Submitted 15 February 2008 ; accepted in final form 2 June 2008


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The administration of insulin is recommended to patients with severe sepsis and hyperglycemia. Previously, we demonstrated that insulin may have direct anti-inflammatory properties and counteracted fluid losses from the circulation by normalizing the interstitial fluid pressure (PIF). PIF is one of the Starling forces determining fluid flux over the capillary wall, and a lowered PIF is one of the driving forces in early edema formation in inflammatory reactions. Here we demonstrate that insulin restores a lipopolysaccharide (LPS)-lowered PIF via a mechanism involving integrin {alpha}vβ3. In C57 black mice (n = 6), LPS lowered PIF from –0.2 ± 0.2 to –1.6 ± 0.3 (P < 0.05) and after insulin averaged –0.8 ± 0.2 mmHg (P = 0.098 compared with after LPS). Corresponding values in wild-type BALB/c mice (n = 5) were –0.8 ± 0.1, –2.1 ± 0.3 (P < 0.05), and –0.8 ± 0.3 mmHg (P < 0.05 compared with LPS) after insulin administration. In BALB/c integrin β3-deficient (β3–/–) mice (n = 6), LPS lowered PIF from –0.1 ± 0.2 to –1.5 ± 0.3 mmHg (P < 0.05). Insulin did not, however, restore PIF in these mice (averaged –1.7 ± 0.3 mmHg after insulin administration). Cell-mediated collagen gel contraction can serve as an in vitro model for in vivo measurements of PIF. Insulin induced {alpha}vβ3-integrin-dependent collagen gel contraction mediated by C2C12 cells. Our findings suggest a beneficiary effect of insulin for patients with sepsis with regard to the fluid balance, and this effect may in part be due to a normalization of PIF by a mechanism involving the integrin {alpha}vβ3.

glucose-insulin-potassium treatment; tissue fluid balance; inflammation

THE INTERSTITIAL FLUID PRESSURE (PIF) is involved in control of the fluid flux across the capillary wall (2). Normally PIF will act to maintain interstitial volume and counteract increased fluid filtration as a function of the interstitial compliance. This is part of the autoregulation of the interstitial fluid volume (17, 23). Contrary to this, a series of studies have demonstrated that PIF can act as an active driving force for edema formation. It has been suggested that connective tissue cells actively control PIF by exerting a tension on the collagen/microfibrillar network of the tissue, thereby restraining the tissue and preventing the hyaluronan and proteoglycan ground substance of the connective tissue from taking up fluid and swelling (31). The addition of anti-integrin β1 IgG or anti-integrin {alpha}2β1 IgG to rat dermis causes a lowering of PIF, suggesting that β1-integrins mediate cellular tension on the collagen/microfibrillar network during fluid homeostasis (24). We have proposed a model where we suggest that the lowering of PIF seen in inflammatory reactions is caused by an impairment of β1-integrin function. This results in connective tissue cells releasing their tension on the connective tissue molecules and thereby allowing the ground substance to take up fluid and swell, leading to an edema.

Cell-mediated collagen gel contraction is an in vitro method where the ability of cells to compact a collagen gel is studied. Cell-mediated collagen gel contraction can be used as an in vitro model for cellular control of PIF in vivo. This notion is based on the observation of similarities between the two processes, i.e., a number of substances that have been shown to inhibit collagen gel contraction also lower PIF, and substances that have been shown to stimulate collagen gel contraction also raise a lowered PIF. Thus anti-β1-integrin IgG, prostaglandin E1, and interleukin (IL)-1 inhibit collagen gel contraction (4, 15, 27) and lower PIF (4, 15, 20), whereas PDGF-BB and prostaglandin F2{alpha} stimulate collagen gel contraction and restore a lowered PIF to control levels (4, 10, 24). PDGF-BB normalizes a lowered PIF back to control levels in mouse dermis by a process that depends on integrin {alpha}vβ3 (15). Furthermore, the stimulation of cells with PDGF-BB enables {alpha}vβ3-mediated contraction of collagen gels in vitro (5, 8, 15).

Insulin restores a lowered PIF to control levels (from –0.7 in the control situation to –2.0 after LPS exposure, and then back to –0.4 mmHg after insulin administration) in rat dermis, suggesting that insulin may counteract inflammation-induced edema formation (20). Furthermore, an anti-inflammatory effect of insulin was suggested since the continuous glucose-insulin-potassium treatment lowered plasma and interstitial fluid levels of the proinflammatory cytokines TNF-{alpha} and IL-1β in a sepsis model and also reduced the acute albumin extravasation (20).

The clinical trials with insulin therapy in the intensive care unit (ICU) show conflicting results. Intensive insulin therapy was shown to reduce morbidity and mortality in critically ill patients hospitalized in the surgical ICU (29). These results on mortality could not be reproduced in a later study from the medical ICU (28), and the place for insulin therapy is still debated. The Surviving Sepsis Campaign (6) recommends the use of insulin to control hyperglycemia in patients with severe sepsis, after stabilization in the ICU. The potentially beneficial effect of insulin may be direct, as an anti-inflammatory agent (20), or indirect via strict blood glucose control (28).

Considering the similarities between in vitro collagen gel contraction and in vivo measurement of PIF together with the observation that PDGF-BB restores a lowered PIF in a process dependent on {alpha}vβ3-integrins, we hypothesized that 1) insulin stimulates cell-mediated collagen gel contraction and 2) insulin restores a lowered PIF in a process dependent on {alpha}vβ3-integrins. The present study was performed to test these hypotheses. Briefly, we demonstrated that insulin normalized a PIF lowered by LPS in a process dependent on integrin {alpha}vβ3.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals. Female C57BL/6J mice (n = 26) were from Møllegaard (Lille Skensved). Wild-type and integrin β3-deficient mice on C57BL/6-129S4 background (11, 19) were backcrossed for seven generations against BALB/c mice (Jackson, Bar Harbor, ME) in the Massachusetts Institute of Technology (MIT) facility and donated by Dr. Richard Hynes (MIT). These mice are viable and fertile and were bred in our own animal facility. Both male and female (11 wild-type and 10 integrin β3 deficient) mice were used. Mice were fed ad libitum before experiments and anesthetized with a 0.2–0.3-ml subcutaneous injection of ketamine (12.2 mg/ml; Ketalar, Pfizer, New York, NY) combined with medetomidine (24.3 µg/ml; Domitor, Orion Pharma, Espoo, Finland). Additional anesthetics were administered when needed. The mice were catheterized in the external jugular vein for intravenous injections. Circulatory arrest was induced by an intravenous injection of saturated KCl. Experiments were performed with the approval of and in accordance with the recommendations laid down by the Norwegian State Commission for Laboratory Animals.

Cells and cell culture. Murine C2C12 myoblast cells, from the American Type Culture Collection, were kindly provided by Dr. A. Starzinski-Powitz. C2C12 cells lack collagen-binding β1-integrins and do not mediate collagen gel contraction in the absence of exogenous stimulators (26). C2C12-{alpha}2 cells are C2C12 cells transfected with human full-length integrin {alpha}2 cDNA and have been described earlier (26). These cells express integrin {alpha}2β1 as the only collagen-binding integrin. Cells were kept in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (both from GIBCO; Gaithersburg, MD), 60 µg/ml penicillin, and 50 µg/ml streptomycin at 37°C with 5% CO2-95% room air.

Collagen gel contraction. Collagen gel contractions were performed as previously described (9). Briefly, 96-well plates (Sarstedt, Nümbrecht, Germany) were blocked in BSA overnight at 37°C and washed with PBS. Cells were washed two times in DMEM and mixed with a collagen solution containing five parts 2x DMEM, one part 0.2 mol/l HEPES (pH 8.0), and four parts collagen type I (Vitrogen 100, Cohesion, Palo Alto, CA) to a final concentration of 100,000 cells/ml. When indicated, anti-integrin β1 IgM (10 µg/ml final concentration; Ha2/5, BD Pharmingen, San Diego, CA) and/or an integrin {alpha}v inhibitor [10 µmol/l final concentration, cyclo-(Arg-Gly-Asp-D-Phe-Val); Bachem, Bubendorf, Switzerland] were added to the cell/collagen suspension. Cell/collagen suspension (100 µl) was transferred to each well in the 96-well plates, and the plates were left in 37°C for 1.5 h for gels to form. The gels were then detached from the walls of the wells by injection of 100 µl DMEM into each well. When indicated, insulin (Insuman Rapid, Aventis Pharma, Paris, France) was added to the flotation media (0.1 IU/ml final concentration). The relaxed, floating gels were further incubated at 37°C, and gel diameters were measured microscopically at the indicated time points. Contraction is presented as the gel area in percentage of the original gel area. Each experiment was repeated three times with a minimum of six gels per condition.

PIF measurements. PIF was measured using sharpened glass capillaries filled with 0.3 M NaCl colored with Evans blue and connected to a servo-controlled counterpressure system (30). The punctures were performed through intact skin using a stereomicroscope (Wild M5, Heerbrugg, Switzerland). Care was taken not to cause any compression or retraction of the skin while puncturing. The animal was placed in a supine position, and the left hind paw was carefully fixed to the table with surgical tape. Control PIF was measured with the circulation still intact. NaCl (controls) or 10 µg LPS (Sigma, St. Louis, MO) in 0.1 ml 0.9% NaCl was injected intravenously and allowed to circulate for 2 min before circulatory arrest was induced. Circulatory arrest was induced to prevent a potential underestimation of the lowered PIF due to increased interstitial fluid volume as a result of increased transcapillary fluid flux. The PIF was monitored for 30 min, and 0.5 µl insulin, 0.1 IE/ml Actrapid (Novo Nordisk, diluted in 0.9% NaCl) was then injected subdermally using a 10-µl chromatography syringe (Hamilton). Measurements were then continued for another 30 min at the edge of the injected volume, and all measurements were preformed at the same distance from the injection site, visually controlled. The pressure measurements were averaged in 15-min periods. For a measurement to be accepted, the following criteria had to be fulfilled: 1) feedback gain could be changed without changing the pressure, and 2) applying suction to the pipette by the pump increased the resistance in the pipette (this ensured contact between the pipette and the interstitial fluid, i.e., that the pipette was open), and 3) zero pressure did not change during the measurement.

Statistical analysis. One-way ANOVA and subsequent Bonferroni post hoc tests were used for each experimental group, comparing control, 15 to 30 min, and 45 to 60 min. Thereafter, the groups were compared against each other for the specific periods. For the in vitro gel experiments, Student's t-tests were used. Results are presented as means ± SE. P < 0.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
C2C12 cells lack collagen-binding β1-integrins and do not mediate collagen gel contraction in the absence of exogenous stimulators. Insulin at a concentration of 0.1 IU/ml induced C2C12-mediated contraction (Fig. 1). The addition of 10 µM of a cyclic Arg-Gly-Asp (RGD) peptide, which specifically inhibits integrin {alpha}vβ3, abolished the stimulatory effect of insulin (Fig. 1).


Figure 1
View larger version (9K):
[in this window]
[in a new window]

  		Fig. 1. Insulin stimulated collagen gel contraction by C2C12 cells in an integrin {alpha}vβ3-dependent manner. Collagen gel contractions were performed as described in MATERIALS AND METHODS. Contraction of C2C12 cells was measured for 24 h in the absence (diamonds) or presence (triangles) of an integrin {alpha}v-inhibitor (inh) and in the absence (solid lines, black symbols) or presence (dashed lines, white symbols) of insulin. Data are presented as means ± SE from 3 independent experiments. *P < 0.05 compared with corresponding time point for control.

 
C2C12 cells transfected with integrin {alpha}2-subunit cDNA, which leads to the expression of the collagen-binding integrin {alpha}2β1 (C2C12-{alpha}2 cells), effectively contracted collagen gels also in the absence of exogenous stimulators (Fig. 2A). Also, these cells were stimulated by insulin, but the cyclic RGD peptide had no inhibitory effect (Fig. 2A).


Figure 2
View larger version (11K):
[in this window]
[in a new window]

  		Fig. 2. Effect of insulin on C2C12-{alpha}2-mediated collagen gel contraction. Collagen gel contractions were performed as described in MATERIALS AND METHODS. A: contraction of C2C12-{alpha}2 cells was measured for 24 h in the absence (diamonds) or presence (triangles) of an integrin {alpha}v-inhibitor and in the absence (solid lines, black symbols) or presence (dashed lines, white symbols) of insulin. B: contraction of C2C12-{alpha}2 cells was measured for 24 h in the absence (diamonds) or presence (squares) of anti-integrin β1 IgM and in the absence (solid lines, black symbols) or presence (dashed lines, white symbols) of insulin. C: contraction of C2C12-{alpha}2 cells was measured for 24 h in the absence (diamonds) or presence (crosses) of an integrin {alpha}v-inhibitor in combination with anti-integrin β1 IgM and in the absence (solid lines) or presence (dashed lines) of insulin. Data are presented as means ± SE from 3 independent experiments. *P < 0.05 compared with corresponding time point for control.

 
Anti-integrin β1 IgM inhibited C2C12-{alpha}2 cell-mediated contraction, and this inhibition could be partly overcome by insulin (Fig. 2B). The combination of anti-integrin β1 IgM and the cyclic RGD peptide, however, completely inhibited contraction by C2C12-{alpha}2 cells (Fig. 2C).

As has been shown in rat dermis (20), the intravenous injection of LPS significantly decreased PIF in C57BL/6J mouse dermis (Fig. 3A, and Table 1). After an initial decrease in PIF, the subdermal injection of insulin restored PIF to control levels (Fig. 3A, and Table 1). The subdermal injection of NaCl did not normalize a LPS-induced lowering of PIF, and, in addition, a subdermal injection of insulin in naive dermis had no effect on PIF (Fig. 3A, and Table 1).


Figure 3
View larger version (14K):
[in this window]
[in a new window]

  		Fig. 3. Effect of insulin on interstitial fluid pressure (PIF) following LPS inflammation. PIF measurements were performed as described in MATERIALS AND METHODS. In contrast to insulin (dashed lines), NaCl (solid lines) did not restore PIF when injected subdermally (sd). iv, Intravenously. BALB/c β3+/+ mice (diamonds, B) behaved like commercially available C57BL/6J mice (A). In BALB/c β3–/– mice insulin did not restore the reduced PIF (B, triangle, dashed line). Values represent fall in PIF after LPS/NaCl injection. Control values are set to 0 mmHg. Data are presented as means ± SE. For absolute PIF values and statistical analysis, see Table 1.

 

View this table:
[in this window]
[in a new window]

  		Table 1. PIF in mouse dermis

 
LPS also lowered PIF in BALB/c mice (Fig. 3B, and Table 1). The lowering of PIF from control levels following LPS was significant, and with the same magnitude as for the C57BL/6J mice. A subsequent subdermal injection of insulin after the lowering of PIF normalized PIF when injected in wild-type mice but not in integrin β3-deficient BALB/c mice (Fig. 3B, and Table 1). These results show that insulin has an effect on PIF under LPS inflammation that is dependent on β3-integrins.


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Here we show that integrin {alpha}vβ3 acts downstream of ligand-stimulated insulin receptors and/or insulin-like growth factor receptor-1 (IGF-R1) in normalizing dermal PIF, which had been lowered by LPS-induced inflammation. The mechanism by which insulin normalized PIF most likely involves the contraction of the loose connective tissues surrounding the blood vessels. This notion is based on the present findings as follows: 1) insulin normalized PIF when the blood circulation was arrested during the time of measurement, excluding the possibility that endothelial cells or plasma proteins participated in fluid transport and changes of PIF; and 2) insulin induced integrin {alpha}vβ3-mediated collagen gel contraction by in vitro cultured cells lacking collagen-binding β1-integrins.

PDGF-BB (15) and insulin (present study) depend on integrin {alpha}vβ3 and have similar effects on PIF and collagen gel contraction, making it likely that the two factors elicit common intracellular signal pathways controlling contraction. Our laboratory (10) has previously shown that the activation of phosphatidylinositol 3-kinase (PI3K) by ligand-stimulated PDGF β-receptors is crucial for PDGF-BB-stimulated normalization of PIF and cell-mediated collagen gel contraction. Similarly, the ability of insulin to normalize a lowered PIF involves the activation of PI3K (20). In addition, the inhibition of PI3K in naive dermis lowers PIF (1). Together, these findings suggest that insulin and PDGF-BB elicit a common PI3K-dependent signaling pathway that promotes cellular contraction and that is of importance in the control of PIF.

Insulin signaling is mediated mainly through the insulin receptor although insulin also binds and stimulates the structurally similar IGF-R1, albeit with substantially lower affinity, as well as the IGF-R1/insulin receptor hybrid receptors (18, 21, 25). IGF-1 that binds and activates IGF-R1 stimulates fibroblast-mediated collagen gel contraction (12, 14). It is currently not known whether insulin exerts its effects on PIF through the stimulation of the insulin receptors or IGF-R1.

The results presented here suggest that insulin, similar to PDGF-BB (15), induced collagen gel contraction by a mechanism that involves integrin {alpha}vβ3. Insulin-induced contraction mediated by C2C12 cells that lack collagen-binding β1- integrins was completely dependent on integrin {alpha}vβ3. The contraction mediated by C2C12-{alpha}2 cells, which express integrin {alpha}2β1, also proceeded in the absence of exogenous stimulation (autocontraction). In contrast to C2C12 cells, neither the autocontraction nor the stimulatory effect of insulin on C2C12-{alpha}2 cells was dependent on integrin {alpha}vβ3. However, C2C12 {alpha}2-mediated contraction was only partly dependent on integrin {alpha}2β1. To completely block the contraction by C2C12-{alpha}2 cells, the blockage of both {alpha}vβ3 and {alpha}2β1 was needed. This suggests a subordinate role for {alpha}vβ3-integrins when functional collagen-binding β1-integrins are present. We and others have previously shown that integrin {alpha}vβ3 can mediate collagen gel contraction but only when β1-integrins are absent or perturbed, and the results presented here are consistent with that (5, 8, 15). In this study it is demonstrated by the fact that the cyclic RGD peptide does not have an effect on integrin {alpha}2β1-mediated contraction, but once that contraction is blocked, the {alpha}vβ3-mediated contraction becomes evident.

The collagen gel contraction is an established model for wound contraction and tissue remodeling in vitro (3). We have used this in vitro assay to investigate and evaluate the in vivo control of PIF (4, 10, 15). So far, the results obtained in the collagen gel contraction have been parallel to the in vivo observations, i.e., agents that enhance contraction attenuate a lowering of PIF, whereas agents that slow the contraction will lower PIF. In this study such experiments were performed using the murine myoblastic C2C12 cells. These cells were chosen since they lack the endogenous expression of all collagen-binding integrins. This is a prerequisite to be able to investigate contraction mediated by {alpha}vβ3-integrins.

The results discussed above from collagen gel contractions are in agreement with results from in vivo PIF measurements where β1-integrins are responsible for maintenance of PIF under normal conditions, whereas β3-integrins are involved in the restoration of a lowered PIF when β1-integrin function is disrupted (10, 15, 23, 24). As previously demonstrated for PDGF-BB, we now demonstrate that insulin also restored a lowered PIF in an integrin {alpha}vβ3-dependent manner. After a sepsis-induced lowering of PIF, insulin restored PIF to control levels in integrin β3 wild-type but not in integrin β3-deficient mice. Thus insulin used the {alpha}vβ3-integrin for restoring a lowered PIF. Interestingly, insulin had no effect under normal conditions. Only after the initial drop in PIF as a result of the disruption of the collagen-binding integrin function, the effect of insulin became evident. This is in agreement with the in vitro results where inhibition of {alpha}vβ3-integrins had no effect on collagen gel contraction mediated by cells expressing collagen-binding integrins. It is also in agreement with observations using PDGF-BB that, under control conditions, do not influence PIF but will restore a lowered PIF (15, 24). In addition, the expression levels of integrin {alpha}vβ3 are low in normal tissues, whereas the expression is elevated in inflamed tissues and in tumor tissues (7, 32), which also supports the hypothesis that the {alpha}vβ3-integrins have a subordinate role in the presence of functional β1-integrins.

The PIF measurements, after the measurement of a control in vivo pressure, are performed in mice with arrested circulation. This is done to prevent fluid transport from the capillaries into the surrounding tissues, which would be the result of a lowered PIF in the presence of an intact circulation. This in turn would lead to an underestimation of the lowered PIF (22). PIF remains stable for at least 60 min after cardiac arrest in rat and mouse skin (13, 22). In agreement with previous studies, test substances were injected subdermally and the measurements performed intradermally in close vicinity of the injection site.

Integrin {alpha}vβ3 does not bind native triple helical collagen, and the mechanism for its restoration of PIF is not known. One possible mechanism involves fibronectin that could serve as a link between the cells and the collagen fibers. We have shown that PDGF-BB stimulates fibronectin production by cells and that fibronectin can link the cells to the collagen via the {alpha}vβ3-integrins in cell-mediated collagen gel contraction (16). When we consider the similarities between PDGF-BB and insulin in stimulating collagen gel contraction and restoring a lowered PIF, it is tempting to speculate that fibronectin could be involved in insulin-stimulated collagen gel contraction as well.

Swelling and edema are some of the cardinal signs of inflammation. During sepsis, extensive plasma leakage, leading to edema, hypotension, and organ dysfunction, may occur. During the last few years, there has been a great focus on the potentially beneficial effect of insulin administration to patients in the ICU. Most of the emphasis has been placed on using insulin to achieve strict blood glucose control in the critically ill patients, but a potentially direct effect of insulin in itself has also been advocated. Given the fact that insulin has a wide variation of responses in different cells and tissues, it is no surprise that the mechanism and organ of target for insulin therapy is still debated. Here we show one of the possible mechanisms for the effects of insulin in sepsis. The fluid filtration over the capillaries is affected by insulin in a mechanism involving the connective tissue and the {alpha}vβ3-integrin, and the process will only become evident after perturbing the functions of β1-integrins.

To summarize, the present study has demonstrated that insulin normalized a PIF lowered by LPS in a process dependent on integrin {alpha}vβ3.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
The study received financial support from the Research Council of Norway, the Western Norway Regional Health Authority, the Swedish Research Council, and the Swedish Cancer Foundation.


   FOOTNOTES
 

Address for reprint requests and other correspondence: Ø. S. Svendsen, Dept. of Biomedicine, Univ. of Bergen, Jonas Lies vei 91, N-5009 Bergen, Norway (e-mail: oyvind.svendsen{at}biomed.uib.no)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

* Ø. S. Svendsen and Å. Lidén contributed equally to this work. Back


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Ahlén K, Berg A, Stiger F, Tengholm A, Siegbahn A, Gylfe E, Reed RK, Rubin K. Cell interactions with collagen matrices in vivo and in vitro depend on phosphatidylinositol 3-kinase and free cytoplasmic calcium. Cell Adhes Commun 5: 461–473, 1998.[Web of Science][Medline]
  2. Aukland K, Reed RK. Interstitial-lymphatic mechanisms in the control of extracellular fluid volume. Physiol Rev 73: 1–78, 1993.[Abstract/Free Full Text]
  3. Bell E, Ivarsson B, Merrill C. Production of a tissue-like structure by contraction of collagen lattices by human fibroblasts of different proliferative potential in vitro. Proc Natl Acad Sci USA 76: 1274–1278, 1979.[Abstract/Free Full Text]
  4. Berg A, Ekwall AK, Rubin K, Stjernschantz J, Reed RK. Effect of PGE1, PGI2, and PGF2{alpha} analogs on collagen gel compaction in vitro and interstitial pressure in vivo. Am J Physiol Heart Circ Physiol 274: H663–H671, 1998.[Abstract/Free Full Text]
  5. Cooke ME, Sakai T, Mosher DF. Contraction of collagen matrices mediated by {alpha}2β1A and {alpha}vβ3 integrins. J Cell Sci 113: 2375–2383, 2000.[Abstract]
  6. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 36: 296–327, 2008.[Web of Science][Medline]
  7. Felding-Habermann B, Mueller BM, Romerdahl CA, Cheresh DA. Involvement of integrin {alpha}V gene expression in human melanoma tumorigenicity. J Clin Invest 89: 2018–2022, 1992.[Web of Science][Medline]
  8. Grundström G, Mosher DF, Sakai T, Rubin K. Integrin {alpha}vβ3 mediates platelet-derived growth factor-BB-stimulated collagen gel contraction in cells expressing signaling deficient integrin {alpha}2β1. Exp Cell Res 291: 463–473, 2003.[CrossRef][Web of Science][Medline]
  9. Gullberg D, Tingström A, Thuresson AC, Olsson L, Terracio L, Borg TK, Rubin K. β1 integrin-mediated collagen gel contraction is stimulated by PDGF. Exp Cell Res 186: 264–272, 1990.[CrossRef][Web of Science][Medline]
  10. Heuchel R, Berg A, Tallquist M, Åhlén K, Reed RK, Rubin K, Claesson-Welsh L, Heldin CH, Soriano P. Platelet-derived growth factor β receptor regulates interstitial fluid homeostasis through phosphatidylinositol-3' kinase signaling. Proc Natl Acad Sci USA 96: 11410–11415, 1999.[Abstract/Free Full Text]
  11. Hodivala-Dilke KM, McHugh KP, Tsakiris DA, Rayburn H, Crowley D, Ullman-Cullere M, Ross FP, Coller BS, Teitelbaum S, Hynes RO. β3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival. J Clin Invest 103: 229–238, 1999.[Web of Science][Medline]
  12. Kanekar S, Borg TK, Terracio L, Carver W. Modulation of heart fibroblast migration and collagen gel contraction by IGF-I. Cell Adhes Commun 7: 513–523, 2000.[Web of Science][Medline]
  13. Karlsen TV, Iversen VV, Forsberg E, Kjellén L, Reed RK, Gjerde EA. Neurogenic inflammation in mice deficient in heparin-synthesizing enzyme. Am J Physiol Heart Circ Physiol 286: H884–H888, 2004.[Abstract/Free Full Text]
  14. Lee YR, Oshita Y, Tsuboi R, Ogawa H. Combination of insulin-like growth factor (IGF)-I and IGF-binding protein-1 promotes fibroblast-embedded collagen gel contraction. Endocrinology 137: 5278–5283, 1996.[Abstract]
  15. Lidén Å, Berg A, Nedrebø T, Reed RK, Rubin K. Platelet-derived growth factor BB-mediated normalization of dermal interstitial fluid pressure after mast cell degranulation depends on β3 but not β1 integrins. Circ Res 98: 635–641, 2006.[Abstract/Free Full Text]
  16. Lidén Å, van Wieringen T, Lannergård J, Kassner A, Heinegård D, Reed RK, Guss B, Rubin K. A secreted collagen- and fibronectin-binding streptococcal protein modulates cell-mediated collagen gel contraction and interstitial fluid pressure. J Biol Chem 283: 1234–1242, 2008.[Abstract/Free Full Text]
  17. Lund T, Wiig H, Reed RK. Acute postburn edema: role of strongly negative interstitial fluid pressure. Am J Physiol Heart Circ Physiol 255: H1069–H1074, 1988.[Abstract/Free Full Text]
  18. Massague J, Czech MP. The subunit structures of two distinct receptors for insulin-like growth factors I and II and their relationship to the insulin receptor. J Biol Chem 257: 5038–5045, 1982.[Free Full Text]
  19. McHugh KP, Hodivala-Dilke K, Zheng MH, Namba N, Lam J, Novack D, Feng X, Ross FP, Hynes RO, Teitelbaum SL. Mice lacking β3 integrins are osteosclerotic because of dysfunctional osteoclasts. J Clin Invest 105: 433–440, 2000.[Web of Science][Medline]
  20. Nedrebø T, Karlsen TV, Salvesen GS, Reed RK. A novel function of insulin in rat dermis. J Physiol 559: 583–591, 2004.[Abstract/Free Full Text]
  21. Pavelic J, Matijevic T, Knezevic J. Biological and physiological aspects of action of insulin-like growth factor peptide family. Indian J Med Res 125: 511–522, 2007.[Web of Science][Medline]
  22. Reed RK, Rodt SÅ. Increased negativity of interstitial fluid pressure during the onset stage of inflammatory edema in rat skin. Am J Physiol Heart Circ Physiol 260: H1985–H1991, 1991.[Abstract/Free Full Text]
  23. Reed RK, Rubin K, Wiig H, Rodt SÅ. Blockade of β1-integrins in skin causes edema through lowering of interstitial fluid pressure. Circ Res 71: 978–983, 1992.[Abstract/Free Full Text]
  24. Rodt SÅ, Åhlén K, Berg A, Rubin K, Reed RK. A novel physiological function for platelet-derived growth factor-BB in rat dermis. J Physiol 495: 193–200, 1996.[Abstract/Free Full Text]
  25. Sachdev D, Yee D. Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol Cancer Ther 6: 1–12, 2007.[Abstract/Free Full Text]
  26. Tiger CF, Fougerousse F, Grundström G, Velling T, Gullberg D. {alpha}11β1 Integrin is a receptor for interstitial collagens involved in cell migration and collagen reorganization on mesenchymal nonmuscle cells. Dev Biol 237: 116–129, 2001.[CrossRef][Web of Science][Medline]
  27. Tingström A, Heldin CH, Rubin K. Regulation of fibroblast-mediated collagen gel contraction by platelet-derived growth factor, interleukin-1{alpha} and transforming growth factor-β 1. J Cell Sci 102: 315–322, 1992.[Abstract/Free Full Text]
  28. Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R. Intensive insulin therapy in the medical ICU. N Engl J Med 354: 449–461, 2006.[Abstract/Free Full Text]
  29. Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in the critically ill patients. N Engl J Med 345: 1359–1367, 2001.[Abstract/Free Full Text]
  30. Wiig H, Reed RK, Aukland K. Micropuncture measurement of interstitial fluid pressure in rat subcutis and skeletal muscle: comparison to wick-in-needle technique. Microvasc Res 21: 308–319, 1981.[CrossRef][Web of Science][Medline]
  31. Wiig H, Rubin K, Reed RK. New and active role of the interstitium in control of interstitial fluid pressure: potential therapeutic consequences. Acta Anaesthesiol Scand 47: 111–121, 2003.[CrossRef][Web of Science][Medline]
  32. Wilder RL. Integrin {alpha}vβ3 as a target for treatment of rheumatoid arthritis and related rheumatic diseases. Ann Rheum Dis 61, Suppl 2: ii96–ii99, 2002.



This article has been cited by other articles:


Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
O.S. Svendsen, M.M. Barczyk, S.N. Popova, A Liden, D. Gullberg, and H. Wiig
The {alpha}11{beta}1 Integrin Has a Mechanistic Role in Control of Interstitial Fluid Pressure and Edema Formation in Inflammation
Arterioscler Thromb Vasc Biol, November 1, 2009; 29(11): 1864 - 1870.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
295/2/H555    most recent
00161.2008v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Svendsen, O. S.
Right arrow Articles by Reed, R. K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Svendsen, O. S.
Right arrow Articles by Reed, R. K.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2008 by the American Physiological Society.