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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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Neutrophil response to ECM proteins regulates their activity in multiple disease states. a. In the arterial development and progression of atherosclerosis, the activated neutrophil and inflamed EC produce and express proteins that contribute to the formation of the lipid plaque. Accumulation of matrix proteins, including fibrin and collagen, contribute to the immobilization and stabilization of the lipid plaque. Neutrophils and ECs subsequently release proteases and oxidants that destabilize the architecture of the plaque, inducing plaque rupture and immobilization. b. In the post-capillary venule of the lung, neutrophil and EC activation can result in the production of oxidants that damage the surrounding tissue matrix. As neutrophils enter into the remodeled matrix, they continue the process of protease release and continue to remodel the microenvironment, facilitating localized inflammation and irritation, symptomatic of COPD. c. Inflammation in the post-capillary venule contributes to the progression of tumor metastasis. Microvascular EC are activated by tumor-released chemokines to induce neutrophil adhesion and tissue infiltration. Neutrophils release oxidants and proteases that remodel the microenvironment, aiding in tumor cell recruitment to pre-metastatic tissues.
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Figure 1: Neutrophil response to ECM proteins regulates their activity in multiple disease states. a. In the arterial development and progression of atherosclerosis, the activated neutrophil and inflamed EC produce and express proteins that contribute to the formation of the lipid plaque. Accumulation of matrix proteins, including fibrin and collagen, contribute to the immobilization and stabilization of the lipid plaque. Neutrophils and ECs subsequently release proteases and oxidants that destabilize the architecture of the plaque, inducing plaque rupture and immobilization. b. In the post-capillary venule of the lung, neutrophil and EC activation can result in the production of oxidants that damage the surrounding tissue matrix. As neutrophils enter into the remodeled matrix, they continue the process of protease release and continue to remodel the microenvironment, facilitating localized inflammation and irritation, symptomatic of COPD. c. Inflammation in the post-capillary venule contributes to the progression of tumor metastasis. Microvascular EC are activated by tumor-released chemokines to induce neutrophil adhesion and tissue infiltration. Neutrophils release oxidants and proteases that remodel the microenvironment, aiding in tumor cell recruitment to pre-metastatic tissues.

Mentions: While neutrophil-EC interactions have been investigated in various disease models, the role of matrix protein regulation of neutrophil activity has been underappreciated and may provide multiple therapeutic opportunities for inflammation related disorders including sepsis and arthritis [29-32]. This review will examine the current literature describing the effects of matrix proteins on neutrophil-EC interaction and its relevance to three different disease models: 1) atherosclerosis, 2) COPD, and 3) tumor growth and progression. We hope to summarize the results so far and identify opportunities for further research. Figure 1 illustrates important neutrophil-ECM interactions across these disease models.


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)

Neutrophil response to ECM proteins regulates their activity in multiple disease states. a. In the arterial development and progression of atherosclerosis, the activated neutrophil and inflamed EC produce and express proteins that contribute to the formation of the lipid plaque. Accumulation of matrix proteins, including fibrin and collagen, contribute to the immobilization and stabilization of the lipid plaque. Neutrophils and ECs subsequently release proteases and oxidants that destabilize the architecture of the plaque, inducing plaque rupture and immobilization. b. In the post-capillary venule of the lung, neutrophil and EC activation can result in the production of oxidants that damage the surrounding tissue matrix. As neutrophils enter into the remodeled matrix, they continue the process of protease release and continue to remodel the microenvironment, facilitating localized inflammation and irritation, symptomatic of COPD. c. Inflammation in the post-capillary venule contributes to the progression of tumor metastasis. Microvascular EC are activated by tumor-released chemokines to induce neutrophil adhesion and tissue infiltration. Neutrophils release oxidants and proteases that remodel the microenvironment, aiding in tumor cell recruitment to pre-metastatic tissues.
© Copyright Policy - open access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3375712&req=5

Figure 1: Neutrophil response to ECM proteins regulates their activity in multiple disease states. a. In the arterial development and progression of atherosclerosis, the activated neutrophil and inflamed EC produce and express proteins that contribute to the formation of the lipid plaque. Accumulation of matrix proteins, including fibrin and collagen, contribute to the immobilization and stabilization of the lipid plaque. Neutrophils and ECs subsequently release proteases and oxidants that destabilize the architecture of the plaque, inducing plaque rupture and immobilization. b. In the post-capillary venule of the lung, neutrophil and EC activation can result in the production of oxidants that damage the surrounding tissue matrix. As neutrophils enter into the remodeled matrix, they continue the process of protease release and continue to remodel the microenvironment, facilitating localized inflammation and irritation, symptomatic of COPD. c. Inflammation in the post-capillary venule contributes to the progression of tumor metastasis. Microvascular EC are activated by tumor-released chemokines to induce neutrophil adhesion and tissue infiltration. Neutrophils release oxidants and proteases that remodel the microenvironment, aiding in tumor cell recruitment to pre-metastatic tissues.
Mentions: While neutrophil-EC interactions have been investigated in various disease models, the role of matrix protein regulation of neutrophil activity has been underappreciated and may provide multiple therapeutic opportunities for inflammation related disorders including sepsis and arthritis [29-32]. This review will examine the current literature describing the effects of matrix proteins on neutrophil-EC interaction and its relevance to three different disease models: 1) atherosclerosis, 2) COPD, and 3) tumor growth and progression. We hope to summarize the results so far and identify opportunities for further research. Figure 1 illustrates important neutrophil-ECM interactions across these disease models.

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