Comprehensive Physiology Wiley Online Library

The Microcirculation in Inflammation

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Historical Background
2 Anatomy of the Microcirculation: Arterioles, Capillaries, and Venules
3 Special Circulations
4 Types and Ontogeny of White Blood Cells
4.1 Myeloid differentiation
4.2 Neutrophils
4.3 Monocytes
4.4 Tissue‐resident macrophages and dendritic cells
4.5 Mast cells
4.6 Eosinophils and basophils
4.7 Lymphocytes
5 Endothelial Cells in Inflammation
5.1 Endothelial heterogeneity
5.2 Endothelial surface layer
5.3 Endothelial activation
5.4 Endothelial permeability in inflammation
6 Integrated View: The Microcirculation in Inflammation
6.1 Vasomotor responses and consequences for perfusion, blood flow, shear stress
6.2 Classes of chemoattractants
6.3 Inflammatory chemokines and their receptors
6.4 Locally acting cytokines
6.5 Systemic cytokines and chemokines
6.6 Complement activation and its regulation
6.7 Eicosanoids
6.8 Other inflammatory mediators
7 Leukocyte Adhesion Cascade – General Paradigm and Exceptions
8 Leukocyte–Endothelial Interactions
8.1 Leukocyte integrins
8.2 Integrin‐associated molecules
8.3 Leukocyte immunoglobulin‐like adhesion receptors
8.4 L‐selectin
8.5 PSGL‐1 (CD162)
9 Endothelial Adhesion Molecules
9.1 P‐selectin
9.2 E‐selectin
9.3 Endothelial immunoglobulin‐like adhesion molecules
9.4 Other endothelial adhesion molecules
9.5 Signaling through adhesion molecules
9.6 Soluble adhesion molecules
10 Chemokine‐Mediated Arrest of Rolling Leukocytes
10.1 null
10.2 Differential activation of integrins
10.3 Intracellular signaling mediating arrest
11 Transmigration
11.1 null
11.2 Transmigration driven by endothelial cell activation
11.3 Paracellular route
11.4 Transcellular route
11.5 Migration through the endothelial basement membrane and pericyte sheath
11.6 Transmigration of monocytes, T cells, eosinophils
12 Migration in the Interstitial Space
13 Microvascular Damage Secondary to Inflammation
14 Oxygen‐ and Nitrogen‐Derived Radicals
14.1 Antimicrobial activities
14.2 Anti‐ and pro‐inflammatory effects of NO
14.3 Tissue damage by superoxide and other oxygen‐derived radicals
15 Regulation of Inflammatory Responses
15.1 Toll‐like receptors
15.2 Other pattern recognition receptors
15.3 Regulation of inflammation by macrophages and dendritic cells
15.4 Regulation of Inflammation by T cells
15.5 Cytokines regulating inflammation
16 Interaction Between Inflammation and Platelets
16.1 Platelet chemokines
16.2 Platelet chemokine receptors
16.3 Other platelet G‐protein‐coupled receptors
16.4 Platelet cytokines
16.5 Small molecules secreted by platelets
16.6 Platelet‐leukocyte interactions
16.7 Platelet–endothelial interactions
16.8 Enhanced leukocyte adhesion by platelets
17 Interaction Between Inflammation and Coagulation
17.1 Tissue factor
17.2 Proteases of the coagulation cascade
17.3 Fibrinolysis
17.4 Coagulation‐ and fibrinolysis‐induced effects on inflammation
17.5 Inflammation‐induced effects on coagulation and fibrinolysis
18 Resolution of Inflammation
19 Future Work
19.1 Organ‐specific inflammatory processes
19.2 Homeostatic Regulation
19.3 Interactions Between the Innate and Adaptive Immune System
19.4 Pro‐ and Anti‐Inflammatory Strategies
Figure 1. Figure 1.

One of the earliest known images of the microcirculation. Tadpole tail vessels, van Leeuwenhoek (from Ref. ).

Figure 2. Figure 2.

First description of leukocyte rolling. “In the bright space between the flowing blood (a) and the vessel wall, which is surrounded by several parallel fibers, round, bright, and slowly moving lymphocytes can be seen.” Tongue venule of the frog rana temporaria (from Ref. ).

Figure 3. Figure 3.

Leukocyte transmigration. Waller reported that leukocyte could transmigrate after the death of the experimental animal, thus showing that their movement was not driven by blood pressure . The left panel is a drawing of transmigration from Rudolf Virchow , the right panel is from Ref. .

Figure 4. Figure 4.

Leukocyte subsets. Metchnikov (also spelled Metchnikoff) described three types of leukocytes in blood. He distinguished micro‐phages and macrophages (from Ref. ).

Figure 5. Figure 5.

(A) Weibel–Palade bodies. L = lumen. Magnification X20,000. (B) Three Weibel–Palade bodies, two in long section (arrows) showing internal microtubular elements. Note pinocytotic vesicles (arrowheads) and basal lamina (BL), X95,000. (C) A group of Weibel–Palade bodies, showing circular profiles of transversely sectioned microtubular elements. X66,000. From www.pathologyimagesinc.com

Figure 6. Figure 6.

Overlapping shear rate ranges between arterioles and venules. Rolling flux fraction (number of rolling leukocytes per 100 total leukocytes flowing through a microvessel). Top shows data for venules (small open symbols), averages (large open symbols) and arterioles (closed symbols, data from Ref. (originally published as Newtonian wall shear rates) as a function of wall shear rate (1/s) given as Newtonian (8vb/d where vh is blood flow velocity and d is microvessel diameter), the estimate based on platelet tracking (2.1 times higher ) and the most recent and most accurate estimate based on micro‐particle image velocimetry (micro‐PIV, 4.9 times higher ). The bottom panel shows rolling flux fraction in arterioles of TNF‐α treated mouse cremaster muscle; data adapted from Ref. (originally published as platelet‐based estimate). Note overlapping shear rate (and shear stress, not shown) ranges between arterioles and venules. Images adapted to match scales.

Figure 7. Figure 7.

Mechanisms of leukocyte margination. (A) In tapered tubes or microvessels (like venules), red blood cells (open symbols) tend to overtake larger leukocytes (black symbols) because of red cell deform‐ability and higher velocity, thus “pushing” the leukocytes to the wall. (B) Cross‐sectional view of a glass tube or microvessel perfused with whole blood. Aggregating red blood cells occupy the center (not shown) and push white blot cells (dots) toward the wall. (C) Leukocyte (black dot) margination at a confluence, where Q1 < Q2. The stream from Q1 becomes compressed so the leukocyte entering from venule Q1 is forced toward the wall. Note different scales of panels (from Ref. ).

Figure 8. Figure 8.

Microcorrosion casts from normal spleen, showing three‐dimensional relationship between arterial tree (A), a lymphatic nodule (white pulp corroded away), and the surrounding marginal sinus (MS) and marginal zone (MZ). Note the sparcity of vessels within nodule, typical of normal spleens. Bar = 50μm. (B) MS consists of flattened, anastomosing vascular spaces between lymphatic nodule and MZ. Note sheetlike appearance of MS versus knobby configuration of MZ. One region of MS is fragmented (→) due to incomplete filling. The opening in MS (*) is the site where the central artery (cast accidentally broken off) entered nodule. Bar = 50mm (from Ref. ).

Figure 9. Figure 9.

Sheet flow in the lung. (A) Transmission EM of interal‐veolar septum of the lung of the vervet monkey, Cercopithecus aethiops showing capillary blood exposed to air on all sides, w, alveolar macrophage; r, erythrocyte; ○, blood–gas barrier; a, alveoli. x3088. (B) Scanning EM of edge of an interalveolar septum of the lung of the vervet monkey, Cercopithecus aethiops, showing blood capillaries (i) and connective tissue septa (○) separating the blood capillaries. →, erythrocyte. n, interalveolar pore. x1240 (from Ref. [).

Figure 10. Figure 10.

Liver microcirculation visualized by intravital microscopy. Concanavalin A treatment increases lymphocyte (bright cells) rolling and adhesion in the postsinusoidal venules (A) as well as sinusoids (arrows in B) (from Ref. ).

Figure 11. Figure 11.

Kidney microcirculation visualized by corrosion casting. Normal kidney cortex depicting the parallel array of interlobular arteries, an interlobular vein (white arrow), and glomeruli (G). The peritubular capillary network homogeneously fills all the space between the other structures (A: Bar = 100μm per division; B: bar = 500μm per division) (from Ref. ).

Figure 12. Figure 12.

Hematopoietic ontogeny in adults. Long‐term hematopoietic stem cells (LT‐HSC) can self‐renew or differentiate to short‐term (ST)‐HSC. CLP, common lymphoid progenitor: CMP. common myeloid progenitor; GMP, granulocyte macrophage progenitor; MEP. megakaryocyte/erythroid progenitor; NK, natural killer (from Ref. ).

Figure 13. Figure 13.

(A) Neutrophils (band and segmented nucleus, human, top), a basophil (bottom left) and eosinophil (bottom right) as seen in peripheral blood smears. All from Wadsworth Center, New York State Department of Health, USA. (B) Neutrophil transmigrating through the wall of a microvessel (top left) into the tissue (bottom right), guinea pig. Freie Universität Berlin, Germany. (C) Platelet–neutrophil aggregate in blood smear. Wadsworth Center, New York State Department of Health, USA. (D) Transmission electron micrograph of a platelet. Sara J. Israels, Manitoba Institute of Cell Biology, Winnipeg, Manitoba, Canada. (E) Platelet in blood, scanning electron micrograph, Monash University, Melbourne, Australia. (F) Time course of the activation of a human platelet on glass imaged with atomic force microscopy. Monika Fritz. Manfred Radmacher, Hermann E. Gaub, Technische Universität München. Germany. (See page 6 in colour section at the back of the book)

Figure 14. Figure 14.

Positive and negative regulation of peripheral T cell differentiation by TGFβ1. Transforming growth factor‐β1 (TGFβ1) has opposing effects on the differentiation of different T cell lineages. (A) Differentiation of naïve CD4+ and CD8+ T cells into T helper 1 (TH1) cells, TH2 cells or cytotoxic T lymphocytes (CTLs) is opposed by TGF31. (B) The generation of TGFβ1‐producing immunomodulatory T cells, peripheral differentiation of forkhead box P3 (FOXP3)‐expressing regulatory T (Treg) cells and interleukin‐17 (IL‐17) producing TH17 cells is promoted by TGFβ1 signaling. RORγt, retinoic acid receptor‐related orphan receptor‐γt: TR1, T regulatory 1 (from Ref. ). (See page 6 in colour section at the back of the book)

Figure 15. Figure 15.

Endothelial heterogeneity. Peroxidase stain for adhesion molecules. (A) negative control antibody. Expression of ICAM‐1 (D), but not P‐selectin (B) or E‐selectin (C) in resting mouse cremaster venules (from Ref. ). (E) P‐selectin expressed in venule (arrows) but not arteriole after surgical preparation trauma. (F) TNF‐α increases P‐selectin expression in venule (arrow) and induces some in arteriole (arrowhead). E‐selectin without (G) and with (H) TNF‐α (from Ref. ). (I) Confocal image of immunofluorescently labeled P‐selectin in an intact blood perfused venule of the mouse cremaster muscle (left) and a corresponding isotype‐matched control vessel under the same imaging conditions (right) (from Ref. ).

Figure 16. Figure 16.

Consequences of the endothelial surface layer. Nearwall velocity in venule measured by micro‐PIV . Delay between double exposures pre‐set in strobe. Left: Intravital microscopy of mouse cremaster venule with two images of the same microbead. ESL is not visible by intravital microscopy, but its presence influences the velocity of the microbeads (schematic diagram on right), because the fluid velocity in the ESL is much smaller than in the lumen. Arrows in diagram indicate bead velocity.

Figure 17. Figure 17.

Adhesion molecules and endothelial surface layer (ESL). Neutrophils interacting with the endothelium lined with a 500‐nm thick ESL (gray) in a postcapillary venule. In capillaries, neutrophils are deformed into a near‐cylindrical shape (A) and deform the ESL. Almost all leukocytes rolling are initiated at the beginning of postcapillary venules, where leukocytes are in close physical contact with the endothelial surface (B). Non‐interacting deformed leukocytes eventually recover their spherical shape (C), but rolling leukocytes, especially neutrophils, acquire a characteristic teardrop shape that reflects the effect of adhesive forces balanced by shear forces on the cytoskeleton (D). Rolling or adherent cells can nucleate L‐selectin‐PSGL‐1‐dependent secondary capture or tethering events (E). A close‐up of a rolling neutrophil (bottom right) shows the endothelial ESL (grey 500 nm) with endothelial adhesion molecules (E‐selectin, 30 nm, and P‐selectin, 40 nm). The black hairlike lines represent the length of a P‐selectin‐PSGL‐1 pair (100nm) completely buried in the ESL. Rolling leukocytes probably continuously deform the ESL as they roll while selectin (and integrin) bonds are formed at the leading edge (right) and broken at the trailing edge (left). Arrows indicate direction of blood flow (figure from Ref. ). (See page 6 in colour section at the back of the book)

Figure 18. Figure 18.

Integrin affinity regulation. Conformational changes in the α and β chains (red and blue), resulting in increased affinity for monovalent ligands. Note that cytoplasmic tails move apart during affinity regulation, probably through interaction with talin (green oval) (modified from Ref. ). (See page 6 in colour section at the back of the book)

Figure 19. Figure 19.

Integrin avidity regulation by lateral mobility/clustering. Transient release of integrins from cytoskeletal anchorage (actin filaments, represented as strings of circles) allows integrin rearrangement and clustering in the plane of the cell membrane, resulting in increased avidity for multivalent ligands. Integrins bind actin through various linker proteins (green ovals and not shown) (modified from Ref. ). (See page 6 in colour section at the back of the book)

Figure 20. Figure 20.

Mammalian integrin subunits and their αβ associations. 8 β subunits can assort with 18 α. subunits to form 24 distinct integrins. These can be considered in several subfamilies based on evolutionary relationships (coloring of α subunits), ligand specificity and, in the case of β2 and β7 integrins, restricted expression on white blood cells, α subunits with gray hatching or stippling have inserted I domains (from Ref. ). (See page 7 in colour section at the back of the book)

Figure 21. Figure 21.

Leukocyte rolling in mouse cremaster venules (∼25mm diameter) without (top) and with (bottom) TNF‐α treatment. In untreated venules, rolling is largely P‐selectin dependent . Although leukocyte rolling flux does not increase after TNF‐α, many more rolling neutrophils are seen per field of view, because the rolling velocity decreases dramatically through E‐selectin and LFA‐1 engagement . Note deformation of rolling cells (arrowhead). Arrow indicates direction of flow.

Figure 22. Figure 22.

(A) Assembly of the phagocyte NADPH oxidase NOX2. In resting neutrophil granulocytes (left), NOX2 and p22phox are found primarily in the membrane of intracellular vesicles. They exist in close association, costabilizing one another. Upon activation (right), there is an exchange of GDP for GTP on Rac leading to its activation. Phosphorylation of the cytosolic p47phox subunit leads to conformational changes allowing interaction with p22phox. The movement of p47phox brings with it the other cytoplasmic subunits, p67phox and p40phox to form the active NOX2 enzyme complex. Once activated, there is a fusion of NOX2‐containing vesicles with the plasma membrane or the phagosomal membrane. The active enzyme complex transports electrons from cytoplasmic NADPH to extracellular or phagosomal oxygen to generate superoxide (O2) (from Ref. ). (B) Myeloperoxidase and other microbicidal products. BPI, bactericidal permeability increasing protein; H2O2, hydrogen peroxide; HOBr, hypobromous acid; HOCI. hypochlorous acid; HOI, hypoiodous acid; MMP, matrix metalloproteinase; 1O2, singlet oxygen; O2, superoxide; O3, ozone; OH, hydroxyl radical; phox, phagocyte oxidase (from Ref. ). (See page 7 in colour section at the back of the book)

Figure 23. Figure 23.

Leukocyte–platelet interactions. Each double arrow indicates a molecular interaction, (modified from Ref. ). (See page 8 in colour section at the back of the book)

Figure 24. Figure 24.

Proinflammatory effects of the coagulation system. The role of protease‐activated receptors (PARs) in the crosstalk between coagulation and inflammation. Tissue factor (TF) expression within the vasculature leads to activation of the coagulation proteases factor VIIa, factor Xa, and thrombin (IIa). Thrombin activates platelets, cleaves fibrinogen, and, when bound to thrombomodulin (TM) in association with the endothelial cell protein C receptor (E). activates protein C to generate activated protein C (APC). Thrombin also activates PAR‐1 and PAR‐4. The TF‐factor VIIa‐factor Xa complex activates PAR‐1 and PAR‐2 (from Ref. ). (See page 8 in colour section at the back of the book)



Figure 1.

One of the earliest known images of the microcirculation. Tadpole tail vessels, van Leeuwenhoek (from Ref. ).



Figure 2.

First description of leukocyte rolling. “In the bright space between the flowing blood (a) and the vessel wall, which is surrounded by several parallel fibers, round, bright, and slowly moving lymphocytes can be seen.” Tongue venule of the frog rana temporaria (from Ref. ).



Figure 3.

Leukocyte transmigration. Waller reported that leukocyte could transmigrate after the death of the experimental animal, thus showing that their movement was not driven by blood pressure . The left panel is a drawing of transmigration from Rudolf Virchow , the right panel is from Ref. .



Figure 4.

Leukocyte subsets. Metchnikov (also spelled Metchnikoff) described three types of leukocytes in blood. He distinguished micro‐phages and macrophages (from Ref. ).



Figure 5.

(A) Weibel–Palade bodies. L = lumen. Magnification X20,000. (B) Three Weibel–Palade bodies, two in long section (arrows) showing internal microtubular elements. Note pinocytotic vesicles (arrowheads) and basal lamina (BL), X95,000. (C) A group of Weibel–Palade bodies, showing circular profiles of transversely sectioned microtubular elements. X66,000. From www.pathologyimagesinc.com



Figure 6.

Overlapping shear rate ranges between arterioles and venules. Rolling flux fraction (number of rolling leukocytes per 100 total leukocytes flowing through a microvessel). Top shows data for venules (small open symbols), averages (large open symbols) and arterioles (closed symbols, data from Ref. (originally published as Newtonian wall shear rates) as a function of wall shear rate (1/s) given as Newtonian (8vb/d where vh is blood flow velocity and d is microvessel diameter), the estimate based on platelet tracking (2.1 times higher ) and the most recent and most accurate estimate based on micro‐particle image velocimetry (micro‐PIV, 4.9 times higher ). The bottom panel shows rolling flux fraction in arterioles of TNF‐α treated mouse cremaster muscle; data adapted from Ref. (originally published as platelet‐based estimate). Note overlapping shear rate (and shear stress, not shown) ranges between arterioles and venules. Images adapted to match scales.



Figure 7.

Mechanisms of leukocyte margination. (A) In tapered tubes or microvessels (like venules), red blood cells (open symbols) tend to overtake larger leukocytes (black symbols) because of red cell deform‐ability and higher velocity, thus “pushing” the leukocytes to the wall. (B) Cross‐sectional view of a glass tube or microvessel perfused with whole blood. Aggregating red blood cells occupy the center (not shown) and push white blot cells (dots) toward the wall. (C) Leukocyte (black dot) margination at a confluence, where Q1 < Q2. The stream from Q1 becomes compressed so the leukocyte entering from venule Q1 is forced toward the wall. Note different scales of panels (from Ref. ).



Figure 8.

Microcorrosion casts from normal spleen, showing three‐dimensional relationship between arterial tree (A), a lymphatic nodule (white pulp corroded away), and the surrounding marginal sinus (MS) and marginal zone (MZ). Note the sparcity of vessels within nodule, typical of normal spleens. Bar = 50μm. (B) MS consists of flattened, anastomosing vascular spaces between lymphatic nodule and MZ. Note sheetlike appearance of MS versus knobby configuration of MZ. One region of MS is fragmented (→) due to incomplete filling. The opening in MS (*) is the site where the central artery (cast accidentally broken off) entered nodule. Bar = 50mm (from Ref. ).



Figure 9.

Sheet flow in the lung. (A) Transmission EM of interal‐veolar septum of the lung of the vervet monkey, Cercopithecus aethiops showing capillary blood exposed to air on all sides, w, alveolar macrophage; r, erythrocyte; ○, blood–gas barrier; a, alveoli. x3088. (B) Scanning EM of edge of an interalveolar septum of the lung of the vervet monkey, Cercopithecus aethiops, showing blood capillaries (i) and connective tissue septa (○) separating the blood capillaries. →, erythrocyte. n, interalveolar pore. x1240 (from Ref. [).



Figure 10.

Liver microcirculation visualized by intravital microscopy. Concanavalin A treatment increases lymphocyte (bright cells) rolling and adhesion in the postsinusoidal venules (A) as well as sinusoids (arrows in B) (from Ref. ).



Figure 11.

Kidney microcirculation visualized by corrosion casting. Normal kidney cortex depicting the parallel array of interlobular arteries, an interlobular vein (white arrow), and glomeruli (G). The peritubular capillary network homogeneously fills all the space between the other structures (A: Bar = 100μm per division; B: bar = 500μm per division) (from Ref. ).



Figure 12.

Hematopoietic ontogeny in adults. Long‐term hematopoietic stem cells (LT‐HSC) can self‐renew or differentiate to short‐term (ST)‐HSC. CLP, common lymphoid progenitor: CMP. common myeloid progenitor; GMP, granulocyte macrophage progenitor; MEP. megakaryocyte/erythroid progenitor; NK, natural killer (from Ref. ).



Figure 13.

(A) Neutrophils (band and segmented nucleus, human, top), a basophil (bottom left) and eosinophil (bottom right) as seen in peripheral blood smears. All from Wadsworth Center, New York State Department of Health, USA. (B) Neutrophil transmigrating through the wall of a microvessel (top left) into the tissue (bottom right), guinea pig. Freie Universität Berlin, Germany. (C) Platelet–neutrophil aggregate in blood smear. Wadsworth Center, New York State Department of Health, USA. (D) Transmission electron micrograph of a platelet. Sara J. Israels, Manitoba Institute of Cell Biology, Winnipeg, Manitoba, Canada. (E) Platelet in blood, scanning electron micrograph, Monash University, Melbourne, Australia. (F) Time course of the activation of a human platelet on glass imaged with atomic force microscopy. Monika Fritz. Manfred Radmacher, Hermann E. Gaub, Technische Universität München. Germany. (See page 6 in colour section at the back of the book)



Figure 14.

Positive and negative regulation of peripheral T cell differentiation by TGFβ1. Transforming growth factor‐β1 (TGFβ1) has opposing effects on the differentiation of different T cell lineages. (A) Differentiation of naïve CD4+ and CD8+ T cells into T helper 1 (TH1) cells, TH2 cells or cytotoxic T lymphocytes (CTLs) is opposed by TGF31. (B) The generation of TGFβ1‐producing immunomodulatory T cells, peripheral differentiation of forkhead box P3 (FOXP3)‐expressing regulatory T (Treg) cells and interleukin‐17 (IL‐17) producing TH17 cells is promoted by TGFβ1 signaling. RORγt, retinoic acid receptor‐related orphan receptor‐γt: TR1, T regulatory 1 (from Ref. ). (See page 6 in colour section at the back of the book)



Figure 15.

Endothelial heterogeneity. Peroxidase stain for adhesion molecules. (A) negative control antibody. Expression of ICAM‐1 (D), but not P‐selectin (B) or E‐selectin (C) in resting mouse cremaster venules (from Ref. ). (E) P‐selectin expressed in venule (arrows) but not arteriole after surgical preparation trauma. (F) TNF‐α increases P‐selectin expression in venule (arrow) and induces some in arteriole (arrowhead). E‐selectin without (G) and with (H) TNF‐α (from Ref. ). (I) Confocal image of immunofluorescently labeled P‐selectin in an intact blood perfused venule of the mouse cremaster muscle (left) and a corresponding isotype‐matched control vessel under the same imaging conditions (right) (from Ref. ).



Figure 16.

Consequences of the endothelial surface layer. Nearwall velocity in venule measured by micro‐PIV . Delay between double exposures pre‐set in strobe. Left: Intravital microscopy of mouse cremaster venule with two images of the same microbead. ESL is not visible by intravital microscopy, but its presence influences the velocity of the microbeads (schematic diagram on right), because the fluid velocity in the ESL is much smaller than in the lumen. Arrows in diagram indicate bead velocity.



Figure 17.

Adhesion molecules and endothelial surface layer (ESL). Neutrophils interacting with the endothelium lined with a 500‐nm thick ESL (gray) in a postcapillary venule. In capillaries, neutrophils are deformed into a near‐cylindrical shape (A) and deform the ESL. Almost all leukocytes rolling are initiated at the beginning of postcapillary venules, where leukocytes are in close physical contact with the endothelial surface (B). Non‐interacting deformed leukocytes eventually recover their spherical shape (C), but rolling leukocytes, especially neutrophils, acquire a characteristic teardrop shape that reflects the effect of adhesive forces balanced by shear forces on the cytoskeleton (D). Rolling or adherent cells can nucleate L‐selectin‐PSGL‐1‐dependent secondary capture or tethering events (E). A close‐up of a rolling neutrophil (bottom right) shows the endothelial ESL (grey 500 nm) with endothelial adhesion molecules (E‐selectin, 30 nm, and P‐selectin, 40 nm). The black hairlike lines represent the length of a P‐selectin‐PSGL‐1 pair (100nm) completely buried in the ESL. Rolling leukocytes probably continuously deform the ESL as they roll while selectin (and integrin) bonds are formed at the leading edge (right) and broken at the trailing edge (left). Arrows indicate direction of blood flow (figure from Ref. ). (See page 6 in colour section at the back of the book)



Figure 18.

Integrin affinity regulation. Conformational changes in the α and β chains (red and blue), resulting in increased affinity for monovalent ligands. Note that cytoplasmic tails move apart during affinity regulation, probably through interaction with talin (green oval) (modified from Ref. ). (See page 6 in colour section at the back of the book)



Figure 19.

Integrin avidity regulation by lateral mobility/clustering. Transient release of integrins from cytoskeletal anchorage (actin filaments, represented as strings of circles) allows integrin rearrangement and clustering in the plane of the cell membrane, resulting in increased avidity for multivalent ligands. Integrins bind actin through various linker proteins (green ovals and not shown) (modified from Ref. ). (See page 6 in colour section at the back of the book)



Figure 20.

Mammalian integrin subunits and their αβ associations. 8 β subunits can assort with 18 α. subunits to form 24 distinct integrins. These can be considered in several subfamilies based on evolutionary relationships (coloring of α subunits), ligand specificity and, in the case of β2 and β7 integrins, restricted expression on white blood cells, α subunits with gray hatching or stippling have inserted I domains (from Ref. ). (See page 7 in colour section at the back of the book)



Figure 21.

Leukocyte rolling in mouse cremaster venules (∼25mm diameter) without (top) and with (bottom) TNF‐α treatment. In untreated venules, rolling is largely P‐selectin dependent . Although leukocyte rolling flux does not increase after TNF‐α, many more rolling neutrophils are seen per field of view, because the rolling velocity decreases dramatically through E‐selectin and LFA‐1 engagement . Note deformation of rolling cells (arrowhead). Arrow indicates direction of flow.



Figure 22.

(A) Assembly of the phagocyte NADPH oxidase NOX2. In resting neutrophil granulocytes (left), NOX2 and p22phox are found primarily in the membrane of intracellular vesicles. They exist in close association, costabilizing one another. Upon activation (right), there is an exchange of GDP for GTP on Rac leading to its activation. Phosphorylation of the cytosolic p47phox subunit leads to conformational changes allowing interaction with p22phox. The movement of p47phox brings with it the other cytoplasmic subunits, p67phox and p40phox to form the active NOX2 enzyme complex. Once activated, there is a fusion of NOX2‐containing vesicles with the plasma membrane or the phagosomal membrane. The active enzyme complex transports electrons from cytoplasmic NADPH to extracellular or phagosomal oxygen to generate superoxide (O2) (from Ref. ). (B) Myeloperoxidase and other microbicidal products. BPI, bactericidal permeability increasing protein; H2O2, hydrogen peroxide; HOBr, hypobromous acid; HOCI. hypochlorous acid; HOI, hypoiodous acid; MMP, matrix metalloproteinase; 1O2, singlet oxygen; O2, superoxide; O3, ozone; OH, hydroxyl radical; phox, phagocyte oxidase (from Ref. ). (See page 7 in colour section at the back of the book)



Figure 23.

Leukocyte–platelet interactions. Each double arrow indicates a molecular interaction, (modified from Ref. ). (See page 8 in colour section at the back of the book)



Figure 24.

Proinflammatory effects of the coagulation system. The role of protease‐activated receptors (PARs) in the crosstalk between coagulation and inflammation. Tissue factor (TF) expression within the vasculature leads to activation of the coagulation proteases factor VIIa, factor Xa, and thrombin (IIa). Thrombin activates platelets, cleaves fibrinogen, and, when bound to thrombomodulin (TM) in association with the endothelial cell protein C receptor (E). activates protein C to generate activated protein C (APC). Thrombin also activates PAR‐1 and PAR‐4. The TF‐factor VIIa‐factor Xa complex activates PAR‐1 and PAR‐2 (from Ref. ). (See page 8 in colour section at the back of the book)

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Klaus Ley. The Microcirculation in Inflammation. Compr Physiol 2011, Supplement 9: Handbook of Physiology, The Cardiovascular System, Microcirculation: 387-448. First published in print 2008. doi: 10.1002/cphy.cp020409