Catálogo de publicaciones - libros

Liver injury is associated with activation of hepatic stellate cells (HSC) to a myofibroblast-like phenotype. In cirrhotic liver injury, activated HSCs are the major source of fibrillar collagens, an excess of which characterise fibrotic matrix. HSCs also have the capacity to remodel this matrix as they express matrix metalloproteinases (MMPs) and their specific inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). Recovery from acute and chronic injury is characterized by apoptosis of the TIMP expressing HSCs thereby relieving the inhibition of matrix degradation. HSC apoptosis is regulated in progressive injury and counterbalances cell proliferation. Apoptosis probably also represents a default pathway for the HSCs resulting from the withdrawal of survival signals after cessation of injury. The survival of activated HSCs in liver injury is dependent on soluble growth factors and cytokines, and on compontents of the fibrotic matrix itself. Additionally, stimulation of death domain receptors expressed on HSCs can precipitate their apoptosis.

Mechanisms that regulate host defense to noninfectious tissue injury are poorly understood. Here we summarize our recent work investigating the role of the innate immune response in regulating the inflammatory and fibrotic response to noninfectious lung injury. We have identified key roles for two cell surface receptors in regulating lung inflammation and fibrosis. CD44 has an essential role in resolving inflammation following noninfectious lung injury. A major function of CD44 in vivo is to clear hyaluronan degradation products that are produced following lung injury. Failure ot clear hyaluronan leads to unremitting inflammation. In contrast, the chemokine receptor CXCR3 has an essential role in limiting the extent of fibrosis following lung injury. This protective effect of CXCR3 in limiting tissue fibroproliferation is mediated, in part, by the innate production of interferon-γ following lung injury. These studies reveal a previously unsuspected role for the innate immune response in regulating inflammation and fibrosis.

Injury to the cornea often leads to corneal fibrosis and scarring resulting in loss of corneal transparency and blindness. Furthermore, current approaches to surgically correct refractive errors, including radial keratotomy (RK), and excimer laser photorefractive keratectomy (PRK) cause damage to the cornea leading to corneal haze and reduced visual acuity. Past studies show that myofibroblasts play a critical role in both the development of wound fibrosis and corneal haze. Myofibroblasts migrate into corneal wounds and establish an interconnected and interwoven contractile network that is necessary for wound contraction, the principal cause of regression following RK. Failure of myofibroblasts to populate the wound results in marked wound gape, mechanical instability and progressive hyperopic refractive changes. Myofibroblasts appearing after PRK also produce marked scattering of light that contributes significantly to corneal haze. In cell culture, myofibroblast differentiate from quiescent stromal cells (keratocytes) after treatment with transforming growth factor-β (TGF-β). Furthermore, treatment of corneal wounds with neutralizing antibodies to TGF-β blocks wound fibrosis and corneal haze after PRK. Recent studies have shown that the differentiation of keratocytes to myofibroblasts involves a synergistic signalling cascade involving integrins, platelet-derived growth factor (PDGF) and TGF-β. These new findings suggest novel therapeutic strategies to modulate myofibroblast differentiation and control corneal wound fibrosis and eliminating corneal haze.