Hypoxia and Inflammation as a Consequence of β-Fibril Accumulation: A Perspective View for New Potential Therapeutic Targets

Table 2

Common clinical features of amyloidosic diseases.

Clinical features	Description and mechanisms	References
Familial	Mutations of the involved protein, strictly influencing misfolding and conformational instability, such as transthyretin in familial amyloidosic polyneuropathy	[72]
Acquired	Conditions presenting abnormal/toxic production and posttransductional misfolding of culprit proteins, such as plasmocytoma (light chains) or chronic inflammatory diseases (SAA) or haemodialysis-related amyloidosis (β2-microglobulin)	[1, 73]
Localized	Organ-limited amyloidosis in which β-fibrils and polymers may became resident, almost stably, in the extracellular space around the cells producing the misfolded protein (see text)	[1]
Systemic	Bulk production and secretion of culprit protein in the extracellular space; protein entering the vessel lumen may be evidenced in blood plasma by a typical electrophoretic peak; accumulation in the extracellular space of distant tissues around the organism (liver, kidney, myocardium, lungs, brain, etc.), such as primary systemic amyloidosis (Ig light chains) and senile systemic amyloidosis (nonmutated transthyretin)	[1]
Progressive	The rate of amyloid accumulation depends not only on the rate of synthesis and on insensitivity to the extracellular proteases but also on the early start and duration length of disease.	[13, 23–25]
False hypertrophy	Both producing cells and accumulating tissues/organs increase their volume at various sizes, depending on the degree of progression.	[23, 74]
Systemic inflammation	A low-degree inflammation is constantly present in a patient bearing amyloidosis. Its intensity level is determined by the strength of the activation mechanisms (see text) and by the nature of the involved protein.	[5, 23, 75]
Hypoxia	There are a few specific studies demonstrating that the space accumulating the amyloid substance is actually hypoxic. However, an accurate evaluation of the distance between the vessels and the peripheral parenchymal cells shows that frequently this is larger than 200 μm, which is the diffusion limit of gas such as oxygen and carbon dioxide.	[3, 76]