Annie Pardo

Role of matrix metalloproteases in pulmonary fibrosis

Lung fibrosis is the final result of a large variety of stimuli including systemic and autoimmune reactions, exposure to organic and inorganic particles, drugs, and radiation. Independent of etiology, the fibrotic response in the lung can be visualized as a dynamic and highly integrated cellular response to persistent injury and may be related to a damage-triggered inflammatory response or to an aberrant epithelial or endothelial reaction. In any case, the key cellular mediator is the myofibroblast, which when activated is the major effector of the lung remodeling. Several matrix metalloproteases (MMPs) have been shown to participate in this pathological process. These enzymes play an essential but complex role in several interrelated processes that take place in the pathogenesis of lung fibrosis including extracellular matrix remodeling, basement membrane disruption, epithelial apoptosis, cell migration, and angiogenesis. This review will focus on the role of MMPs in the development of lung fibrosis.

Hematopoietic Derived Fibrocytes: Emerging Effector Cells in Fibrotic Disorders

Fibrocytes constitute a unique population of mesenchymal progenitor cells from hematopoietic origin. They display a unique spectrum of immune and molecular characteristics such as the simultaneous expression of mesenchymal (collagen types I and III, fibronectin), leukocyte (CD45), monocyte (CD14), and hematopoietic stem cell (CD34) markers. Fibrocytes were initially described in the context of wound repair and since their original description in 1994, our understanding and knowledge of this novel cell population has grown considerably. They have the potential to differentiate into fibroblasts and myofibroblasts among other mesenchymal cells such adipocytes, osteoblasts, and chondrocytes. Fibrocytes are a rich source of inflammatory cytokines, growth factors, and chemokines that provide important intercellular signals within the local tissue microenvironment. Moreover, fibrocytes possess the immunological features typical of an antigen-presenting cell (APC), and they have the capacity for the presentation of antigens to naive T-cells.

Impaired autophagic activity and ATG4B deficiency are associated with increased endoplasmic reticulum stress-induced lung injury

Aging is the main risk factor for the development of idiopathic pulmonary fibrosis (IPF), a progressive and usually lethal lung disorder. Although the pathogenic mechanisms are uncertain, endoplasmic reticulum (ER) stress and impaired proteostasis that have been linked with aging are strongly associated with the pathogenesis of IPF. Using the Atg4b-deficient mice as a model, that partially reproduces the autophagy deficient conditions reported in aging and IPF lungs, we show for the first time how autophagy impairment and ER stress induction, contribute simultaneously to development of lung fibrosis in vivo. Increased expression of ER stress markers, inflammation and apoptosis of alveolar epithelial cells were observed in Atg4b-deficient mice compared to WT mice, when treated with the ER stress inducer tunicamycin. After tunicamycin treatment, Atg4b null lungs showed accumulation of its substrate LC3-I, demonstrating that these mice failed to induce autophagy despite the ER stress conditions. We also showed that compromised autophagy in lungs from Atg4b null mice is associated with exacerbated lung damage, epithelial apoptosis and the development of lung fibrosis at 21 days after tunicamycin treatment. Our findings indicate that ATG4B protein and autophagy are essential to mitigate ER stress and to prevent tunicamycin-induced epithelial apoptosis and lung fibrosis.