14 settembre 2015

articolo postato il: 2015-09-13 17:50:51

L`articolo di questa settimana e` proposto così da DA MARCO DI GIROLAMO:

 

 "Perché può interessare i “fibrillologi” ? C’è un grande interesse sull’interessamento cardiaco da amiloide, quale organo con un particolare “tropismo” per il deposito di fibrille amiloidi rispetto ad altri organi. Inoltre non è del tutto chiaro il motivo per il quale vi possa essere in alcuni casi un notevole ispessimento delle pareti cardiache senza compromissione eccessiva della FE, mentre in altri casi vi è una rapida e catastrofica insufficienza cardiaca. 

Si indica da tempo come i processi dell’infiammazione possano avere una responsabilità nell’accelerare l’inefficienza di un organo. Fibroblasti e miofibroblasti sono stati identificati come “effettori di fibrosi” in molti organi e sono sede di sintesi di proteine della matrice extracellulare attraverso la produzione di una grande varietà di mediatori e  citokine. La fibrosi del tessuto miocardico contribuisce in vario grado alla disfunzione sistolica e diastolica ed ad alterazioni nel sistema di conduzione. E’ stato segnalato [Circulation 2012; 126:1206-16] che il 3% di aumento della frazione del volume extracellulare di tessuto fibroso (dato valutato con RM cardiaca con gadolinio) è associato ad un aumento del 50 % di rischio di eventi cardiaci.

Penso quindi che una strada di ricerca potrebbe essere quella di utilizzare le citokine infiammatorie presenti nelle cardiomiopatie amiloidi per una valutazione del grado di rischio cardiaco (cardiomiopatie amiloidi sistemiche e senili)."

 

 REVIEW ARTICLE

Fibrosis — A Common Pathway to Organ Injury and Failure

Rockey D.C.Bell P.D.Hill J.A

N Engl J Med 2015; 372:   pag. 1138-1149    n 12     March 19, 2015

 

Disease-related injury in any organ triggers a complex cascade of cellular and molecular responses that culminates in tissue fibrosis. Although this fibrogenic response may have adaptive features in the short term, when it progresses over a prolonged period of time, parenchymal scarring and ultimately cellular dysfunction and organ failure ensue (Figure 1).

We and others have proposed four major phases of the fibrogenic response (Figure 2). First is initiation of the response, driven by primary injury to the organ. The second phase is the activation of effector cells, and the third phase is the elaboration of extracellular matrix, both of which overlap with the fourth phase, during which the dynamic deposition (and insufficient resorption) of extracellular matrix promotes progression to fibrosis and ultimately to end-organ failure.

The fact that diverse diseases in different organ systems are associated with fibrotic changes suggests common pathogenic pathways (Figure 2). This “wounding response” is orchestrated by complex activities within different cells in which specific molecular pathways have emerged. Cellular constituents include inflammatory cells (e.g., macrophages and T cells), epithelial cells, fibrogenic effector cells, endothelial cells, and others. Many different effector cells, including fibroblasts, myofibroblasts, cells derived from bone marrow, fibrocytes, and possibly cells derived from epithelial tissues (epithelial-to-mesenchymal transition) have been identified; there is some controversy regarding the identity of specific effectors in different organs. Beyond the multiple cells essential in the wounding response, core molecular pathways are critical; for example, the transforming growth factor beta (TGF-β) pathway is important in virtually all types of fibrosis.

As fibrosis progresses, myofibroblasts proliferate and sense physical and biochemical stimuli in the local environment by means of integrins and cell-surface molecules; contractile mediators trigger pathological tissue contraction. This chain of events, in turn, causes physical organ deformation, which impairs organ function. Thus, the biology of fibrogenesis is dynamic, although the degree of plasticity appears to vary from organ to organ.

Although we understand many of the cellular and molecular processes underlying fibrosis, there are few effective therapies and fewer that target fibrogenesis specifically. These facts highlight the need for a deeper comprehension of the pathogenesis of fibrogenesis and the translation of this knowledge to novel treatments.

figure1
figure2