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The effects of extracellular matrix proteins on neutrophil-endothelial interaction--a roadway to multiple therapeutic opportunities.

Padmanabhan J, Gonzalez AL - Yale J Biol Med (2012)

Bottom Line: These cells are capable of destroying microbes, cell debris, and foreign proteins by oxidative and non-oxidative processes.This area of research presents an opportunity to identify therapeutic targets in inflammation-related diseases.This review will summarize recent literature on the role of neutrophils and the effects of matrix proteins on neutrophil-EC interactions, with focus on three different disease models: 1) atherosclerosis, 2) COPD, and 3) tumor growth and progression.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, School of Engineering and Applied Sciences, Yale University, New Haven, CT 06511, USA.

ABSTRACT
Polymorphoneuclear leukocytes or neutrophils, a major component of white blood cells, contribute to the innate immune response in humans. Upon sensing changes in the microenvironment, neutrophils adhere to the vascular wall, migrate through the endothelial cell (EC)-pericyte bilayer, and subsequently through the extracellular matrix to reach the site of inflammation. These cells are capable of destroying microbes, cell debris, and foreign proteins by oxidative and non-oxidative processes. While primarily mediators of tissue homeostasis, there are an increasing number of studies indicating that neutrophil recruitment and transmigration can also lead to host-tissue injury and subsequently inflammation-related diseases. Neutrophil-induced tissue injury is highly regulated by the microenvironment of the infiltrated tissue, which includes cytokines, chemokines, and the provisional extracellular matrix, remodeled through increased vascular permeability and other cellular infiltrates. Thus, investigation of the effects of matrix proteins on neutrophil-EC interaction and neutrophil transmigration may help identify the proteins that induce pro- or anti-inflammatory responses. This area of research presents an opportunity to identify therapeutic targets in inflammation-related diseases. This review will summarize recent literature on the role of neutrophils and the effects of matrix proteins on neutrophil-EC interactions, with focus on three different disease models: 1) atherosclerosis, 2) COPD, and 3) tumor growth and progression. For each disease model, inflammatory molecules released by neutrophils, important regulatory matrix proteins, current anti-inflammatory treatments, and the scope for further research will be summarized.

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Related in: MedlinePlus

Schematic representation of important regulatory molecules and events during inflammation in atherosclerosis. a. Matrix proteins differentially regulate the activation of EC in response to changes in shear stress applied by blood flow. Fibronectin promotes localized inflammation, while collagen and laminin inhibit flow-induced atherosclerotic inflammation. b. LDL deposits become immobilized by collagen proteins to form atherosclerotic plaques. Meanwhile, platelets, fibrin, and Defensins released by neutrophils contribute to the structural integrity of the developing plaque. c. Subsequently, cytokine-activated neutrophils and ECs release oxidants and proteases that contribute to the destabilization and rupture of lipid plaques. d. Ruptured plaque fracture into the blood stream, entering the heart or brain to induce heart attack or stroke.
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Figure 2: Schematic representation of important regulatory molecules and events during inflammation in atherosclerosis. a. Matrix proteins differentially regulate the activation of EC in response to changes in shear stress applied by blood flow. Fibronectin promotes localized inflammation, while collagen and laminin inhibit flow-induced atherosclerotic inflammation. b. LDL deposits become immobilized by collagen proteins to form atherosclerotic plaques. Meanwhile, platelets, fibrin, and Defensins released by neutrophils contribute to the structural integrity of the developing plaque. c. Subsequently, cytokine-activated neutrophils and ECs release oxidants and proteases that contribute to the destabilization and rupture of lipid plaques. d. Ruptured plaque fracture into the blood stream, entering the heart or brain to induce heart attack or stroke.

Mentions: Neutrophils play a distinct role in the formation of atherosclerotic plaques and atherosclerotic progression. Through production and degradation of plaque protein components, neutrophils are key to the development of atherosclerosis and resulting ischemic reperfusion injury, effectively resulting in myocardial infarction and stroke (Figure 2). In the development of atherosclerotic plaques, activated neutrophils contribute early on through the release of the protein Defensin at the site of EC damage [23,35]. Defensin forms stable complexes with low density lipids that effectively results in further immobilization of the complexes. These complexes bind blood plasma proteins, leading to lipid accumulation and plaque formation [36].


The effects of extracellular matrix proteins on neutrophil-endothelial interaction--a roadway to multiple therapeutic opportunities.

Padmanabhan J, Gonzalez AL - Yale J Biol Med (2012)

Schematic representation of important regulatory molecules and events during inflammation in atherosclerosis. a. Matrix proteins differentially regulate the activation of EC in response to changes in shear stress applied by blood flow. Fibronectin promotes localized inflammation, while collagen and laminin inhibit flow-induced atherosclerotic inflammation. b. LDL deposits become immobilized by collagen proteins to form atherosclerotic plaques. Meanwhile, platelets, fibrin, and Defensins released by neutrophils contribute to the structural integrity of the developing plaque. c. Subsequently, cytokine-activated neutrophils and ECs release oxidants and proteases that contribute to the destabilization and rupture of lipid plaques. d. Ruptured plaque fracture into the blood stream, entering the heart or brain to induce heart attack or stroke.
© Copyright Policy - open access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3375712&req=5

Figure 2: Schematic representation of important regulatory molecules and events during inflammation in atherosclerosis. a. Matrix proteins differentially regulate the activation of EC in response to changes in shear stress applied by blood flow. Fibronectin promotes localized inflammation, while collagen and laminin inhibit flow-induced atherosclerotic inflammation. b. LDL deposits become immobilized by collagen proteins to form atherosclerotic plaques. Meanwhile, platelets, fibrin, and Defensins released by neutrophils contribute to the structural integrity of the developing plaque. c. Subsequently, cytokine-activated neutrophils and ECs release oxidants and proteases that contribute to the destabilization and rupture of lipid plaques. d. Ruptured plaque fracture into the blood stream, entering the heart or brain to induce heart attack or stroke.
Mentions: Neutrophils play a distinct role in the formation of atherosclerotic plaques and atherosclerotic progression. Through production and degradation of plaque protein components, neutrophils are key to the development of atherosclerosis and resulting ischemic reperfusion injury, effectively resulting in myocardial infarction and stroke (Figure 2). In the development of atherosclerotic plaques, activated neutrophils contribute early on through the release of the protein Defensin at the site of EC damage [23,35]. Defensin forms stable complexes with low density lipids that effectively results in further immobilization of the complexes. These complexes bind blood plasma proteins, leading to lipid accumulation and plaque formation [36].

Bottom Line: These cells are capable of destroying microbes, cell debris, and foreign proteins by oxidative and non-oxidative processes.This area of research presents an opportunity to identify therapeutic targets in inflammation-related diseases.This review will summarize recent literature on the role of neutrophils and the effects of matrix proteins on neutrophil-EC interactions, with focus on three different disease models: 1) atherosclerosis, 2) COPD, and 3) tumor growth and progression.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, School of Engineering and Applied Sciences, Yale University, New Haven, CT 06511, USA.

ABSTRACT
Polymorphoneuclear leukocytes or neutrophils, a major component of white blood cells, contribute to the innate immune response in humans. Upon sensing changes in the microenvironment, neutrophils adhere to the vascular wall, migrate through the endothelial cell (EC)-pericyte bilayer, and subsequently through the extracellular matrix to reach the site of inflammation. These cells are capable of destroying microbes, cell debris, and foreign proteins by oxidative and non-oxidative processes. While primarily mediators of tissue homeostasis, there are an increasing number of studies indicating that neutrophil recruitment and transmigration can also lead to host-tissue injury and subsequently inflammation-related diseases. Neutrophil-induced tissue injury is highly regulated by the microenvironment of the infiltrated tissue, which includes cytokines, chemokines, and the provisional extracellular matrix, remodeled through increased vascular permeability and other cellular infiltrates. Thus, investigation of the effects of matrix proteins on neutrophil-EC interaction and neutrophil transmigration may help identify the proteins that induce pro- or anti-inflammatory responses. This area of research presents an opportunity to identify therapeutic targets in inflammation-related diseases. This review will summarize recent literature on the role of neutrophils and the effects of matrix proteins on neutrophil-EC interactions, with focus on three different disease models: 1) atherosclerosis, 2) COPD, and 3) tumor growth and progression. For each disease model, inflammatory molecules released by neutrophils, important regulatory matrix proteins, current anti-inflammatory treatments, and the scope for further research will be summarized.

Show MeSH
Related in: MedlinePlus