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Can the TLR-4-mediated signaling pathway be "a key inflammatory promoter for sporadic TAA"?

Ruvolo G, Pisano C, Candore G, Lio D, Palmeri C, Maresi E, Balistreri CR - Mediators Inflamm. (2014)

Bottom Line: In consistency with these data, a significant association was observed between their combined risk genotype and sporadic TAA.Cases bearing this risk genotype showed higher systemic inflammatory mediator levels, significant inflammatory/immune infiltrate, a typical MD phenotype, lower telomere length, and positive correlations with histopatological abnormalities, hypertension, smoking, and ageing.It might represent a potential useful tool for preventing and monitoring sporadic TAA and developing personalized treatments.

View Article: PubMed Central - PubMed

Affiliation: Unit of Cardiac Surgery, Department of Surgery and Oncology, University of Palermo, 90127 Palermo, Italy.

ABSTRACT
Thoracic aorta shows with advancing age various changes and a progressive deterioration in structure and function. As a result, vascular remodeling (VR) and medial degeneration (MD) occur as pathological entities responsible principally for the sporadic TAA onset. Little is known about their genetic, molecular, and cellular mechanisms. Recent evidence is proposing the strong role of a chronic immune/inflammatory process in their evocation and progression. Thus, we evaluated the potential role of Toll like receptor- (TLR-) 4-mediated signaling pathway and its polymorphisms in sporadic TAA. Genetic, immunohistochemical, and biochemical analyses were assessed. Interestingly, the rs4986790 TLR4 polymorphism confers a higher susceptibility for sporadic TAA (OR = 14.4, P = 0.0008) and it represents, together with rs1799752 ACE, rs3918242 MMP-9, and rs2285053 MMP-2 SNPs, an independent sporadic TAA risk factor. In consistency with these data, a significant association was observed between their combined risk genotype and sporadic TAA. Cases bearing this risk genotype showed higher systemic inflammatory mediator levels, significant inflammatory/immune infiltrate, a typical MD phenotype, lower telomere length, and positive correlations with histopatological abnormalities, hypertension, smoking, and ageing. Thus, TLR4 pathway should seem to have a key role in sporadic TAA. It might represent a potential useful tool for preventing and monitoring sporadic TAA and developing personalized treatments.

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Related in: MedlinePlus

Our model about the pathophysiology of sporadic TAA, the model of the pathway from the double-face. The major risk factors, hypertension, age, and smoking, induce an increased production of reactive oxygen species (ROS) [17–19] and an upregulation of local renin-angiotensin system [16] and the tissue injury, initially involving ECs and subsequently VSMCs. This determines the release of some damage-related products and proteins (i.e., heart shock proteins (HSPs), high-mobility group box-1, low molecular hyaluronic acid, fibronectin fragments, and others), called danger-associated molecular patterns (DAMPs) [20]. DAMPs alert innate/inflammatory immune system interacting with TLR4 mediated signaling pathway, able to recognize both pathogens and endogenous ligands [21, 22]. Originally described as part of the first-line defense against Gram-negative bacteria, the best known member of TLRs, the TLR4, expressed on leukocytes and a large array of tissue and cell types, such as all aortic wall cells (particularly ECs and VSMCs), responds to these signals [23]. As a consequence, TLR4 activates and triggers an inflammatory response [24–28]. In turn, this determines a typical phenotypic switching of EC and VSMC cells due to activation of stress and stretch pathways accompanied by their dysfunction and senescence [27, 28]. In particular, it implies a differential change in their gene expression profile due prevalently of activation of Nuclear Factor-κB (NF-κB) transcription factor and followed by production and release of the so-called arterial-associated senescence secretor phenotype (AASSP) characterized by numerous inflammatory mediators, mitotic and trophic factors, proteoglycans and metalloproteinases (MMP)s, such as MMP-2 and -9, and vasoactive molecules [17, 24–29]. In addition, this also induces the reduction of nitric oxide (NO) [28]. This complex scenario results in modifications of vascular tone and permeability and degradation of components of extracellular matrix (ECM) and elastic fragmentation. VR and MD are, hence, evocated, which can evolve in aneurysm, dissection and rupture of aorta wall [17].
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fig4: Our model about the pathophysiology of sporadic TAA, the model of the pathway from the double-face. The major risk factors, hypertension, age, and smoking, induce an increased production of reactive oxygen species (ROS) [17–19] and an upregulation of local renin-angiotensin system [16] and the tissue injury, initially involving ECs and subsequently VSMCs. This determines the release of some damage-related products and proteins (i.e., heart shock proteins (HSPs), high-mobility group box-1, low molecular hyaluronic acid, fibronectin fragments, and others), called danger-associated molecular patterns (DAMPs) [20]. DAMPs alert innate/inflammatory immune system interacting with TLR4 mediated signaling pathway, able to recognize both pathogens and endogenous ligands [21, 22]. Originally described as part of the first-line defense against Gram-negative bacteria, the best known member of TLRs, the TLR4, expressed on leukocytes and a large array of tissue and cell types, such as all aortic wall cells (particularly ECs and VSMCs), responds to these signals [23]. As a consequence, TLR4 activates and triggers an inflammatory response [24–28]. In turn, this determines a typical phenotypic switching of EC and VSMC cells due to activation of stress and stretch pathways accompanied by their dysfunction and senescence [27, 28]. In particular, it implies a differential change in their gene expression profile due prevalently of activation of Nuclear Factor-κB (NF-κB) transcription factor and followed by production and release of the so-called arterial-associated senescence secretor phenotype (AASSP) characterized by numerous inflammatory mediators, mitotic and trophic factors, proteoglycans and metalloproteinases (MMP)s, such as MMP-2 and -9, and vasoactive molecules [17, 24–29]. In addition, this also induces the reduction of nitric oxide (NO) [28]. This complex scenario results in modifications of vascular tone and permeability and degradation of components of extracellular matrix (ECM) and elastic fragmentation. VR and MD are, hence, evocated, which can evolve in aneurysm, dissection and rupture of aorta wall [17].

Mentions: Finally, our obtained data led us to postulate a potential model about the pathophysiology of sporadic TAA, which might be defined as model of the signaling pathway from the double-face, given its features (see Figure 4). We foretell that it can lead several researchers to perform investigations focused to clear the complex puzzle of this pathology.


Can the TLR-4-mediated signaling pathway be "a key inflammatory promoter for sporadic TAA"?

Ruvolo G, Pisano C, Candore G, Lio D, Palmeri C, Maresi E, Balistreri CR - Mediators Inflamm. (2014)

Our model about the pathophysiology of sporadic TAA, the model of the pathway from the double-face. The major risk factors, hypertension, age, and smoking, induce an increased production of reactive oxygen species (ROS) [17–19] and an upregulation of local renin-angiotensin system [16] and the tissue injury, initially involving ECs and subsequently VSMCs. This determines the release of some damage-related products and proteins (i.e., heart shock proteins (HSPs), high-mobility group box-1, low molecular hyaluronic acid, fibronectin fragments, and others), called danger-associated molecular patterns (DAMPs) [20]. DAMPs alert innate/inflammatory immune system interacting with TLR4 mediated signaling pathway, able to recognize both pathogens and endogenous ligands [21, 22]. Originally described as part of the first-line defense against Gram-negative bacteria, the best known member of TLRs, the TLR4, expressed on leukocytes and a large array of tissue and cell types, such as all aortic wall cells (particularly ECs and VSMCs), responds to these signals [23]. As a consequence, TLR4 activates and triggers an inflammatory response [24–28]. In turn, this determines a typical phenotypic switching of EC and VSMC cells due to activation of stress and stretch pathways accompanied by their dysfunction and senescence [27, 28]. In particular, it implies a differential change in their gene expression profile due prevalently of activation of Nuclear Factor-κB (NF-κB) transcription factor and followed by production and release of the so-called arterial-associated senescence secretor phenotype (AASSP) characterized by numerous inflammatory mediators, mitotic and trophic factors, proteoglycans and metalloproteinases (MMP)s, such as MMP-2 and -9, and vasoactive molecules [17, 24–29]. In addition, this also induces the reduction of nitric oxide (NO) [28]. This complex scenario results in modifications of vascular tone and permeability and degradation of components of extracellular matrix (ECM) and elastic fragmentation. VR and MD are, hence, evocated, which can evolve in aneurysm, dissection and rupture of aorta wall [17].
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4120489&req=5

fig4: Our model about the pathophysiology of sporadic TAA, the model of the pathway from the double-face. The major risk factors, hypertension, age, and smoking, induce an increased production of reactive oxygen species (ROS) [17–19] and an upregulation of local renin-angiotensin system [16] and the tissue injury, initially involving ECs and subsequently VSMCs. This determines the release of some damage-related products and proteins (i.e., heart shock proteins (HSPs), high-mobility group box-1, low molecular hyaluronic acid, fibronectin fragments, and others), called danger-associated molecular patterns (DAMPs) [20]. DAMPs alert innate/inflammatory immune system interacting with TLR4 mediated signaling pathway, able to recognize both pathogens and endogenous ligands [21, 22]. Originally described as part of the first-line defense against Gram-negative bacteria, the best known member of TLRs, the TLR4, expressed on leukocytes and a large array of tissue and cell types, such as all aortic wall cells (particularly ECs and VSMCs), responds to these signals [23]. As a consequence, TLR4 activates and triggers an inflammatory response [24–28]. In turn, this determines a typical phenotypic switching of EC and VSMC cells due to activation of stress and stretch pathways accompanied by their dysfunction and senescence [27, 28]. In particular, it implies a differential change in their gene expression profile due prevalently of activation of Nuclear Factor-κB (NF-κB) transcription factor and followed by production and release of the so-called arterial-associated senescence secretor phenotype (AASSP) characterized by numerous inflammatory mediators, mitotic and trophic factors, proteoglycans and metalloproteinases (MMP)s, such as MMP-2 and -9, and vasoactive molecules [17, 24–29]. In addition, this also induces the reduction of nitric oxide (NO) [28]. This complex scenario results in modifications of vascular tone and permeability and degradation of components of extracellular matrix (ECM) and elastic fragmentation. VR and MD are, hence, evocated, which can evolve in aneurysm, dissection and rupture of aorta wall [17].
Mentions: Finally, our obtained data led us to postulate a potential model about the pathophysiology of sporadic TAA, which might be defined as model of the signaling pathway from the double-face, given its features (see Figure 4). We foretell that it can lead several researchers to perform investigations focused to clear the complex puzzle of this pathology.

Bottom Line: In consistency with these data, a significant association was observed between their combined risk genotype and sporadic TAA.Cases bearing this risk genotype showed higher systemic inflammatory mediator levels, significant inflammatory/immune infiltrate, a typical MD phenotype, lower telomere length, and positive correlations with histopatological abnormalities, hypertension, smoking, and ageing.It might represent a potential useful tool for preventing and monitoring sporadic TAA and developing personalized treatments.

View Article: PubMed Central - PubMed

Affiliation: Unit of Cardiac Surgery, Department of Surgery and Oncology, University of Palermo, 90127 Palermo, Italy.

ABSTRACT
Thoracic aorta shows with advancing age various changes and a progressive deterioration in structure and function. As a result, vascular remodeling (VR) and medial degeneration (MD) occur as pathological entities responsible principally for the sporadic TAA onset. Little is known about their genetic, molecular, and cellular mechanisms. Recent evidence is proposing the strong role of a chronic immune/inflammatory process in their evocation and progression. Thus, we evaluated the potential role of Toll like receptor- (TLR-) 4-mediated signaling pathway and its polymorphisms in sporadic TAA. Genetic, immunohistochemical, and biochemical analyses were assessed. Interestingly, the rs4986790 TLR4 polymorphism confers a higher susceptibility for sporadic TAA (OR = 14.4, P = 0.0008) and it represents, together with rs1799752 ACE, rs3918242 MMP-9, and rs2285053 MMP-2 SNPs, an independent sporadic TAA risk factor. In consistency with these data, a significant association was observed between their combined risk genotype and sporadic TAA. Cases bearing this risk genotype showed higher systemic inflammatory mediator levels, significant inflammatory/immune infiltrate, a typical MD phenotype, lower telomere length, and positive correlations with histopatological abnormalities, hypertension, smoking, and ageing. Thus, TLR4 pathway should seem to have a key role in sporadic TAA. It might represent a potential useful tool for preventing and monitoring sporadic TAA and developing personalized treatments.

Show MeSH
Related in: MedlinePlus