Pulmonary fibrosis: pathogenesis, etiology and regulation

Abstract

Pulmonary fibrosis and architectural remodeling of tissues can severely disrupt lung function, often with fatal consequences. The etiology of pulmonary fibrotic diseases is varied, with an array of triggers including allergens, chemicals, radiation and environmental particles. However, the cause of one of the most common pulmonary fibrotic conditions, idiopathic pulmonary fibrosis (IPF), is still unclear. This review examines common mechanisms of pulmonary wound-healing responses following lung injury, and highlights the pathogenesis of some of the most widespread pulmonary fibrotic diseases. A three phase model of wound repair is reviewed that includes; (1) injury; (2) inflammation; and (3) repair. In most pulmonary fibrotic conditions dysregulation at one or more of these phases has been reported. Chronic inflammation can lead to an imbalance in the production of chemokines, cytokines, growth factors, and disrupt cellular recruitment. These changes coupled with excessive pro-fibrotic IL-13 and/or TGFbeta1 production can turn a well-controlled healing response into a pathogenic fibrotic response. Endogenous regulatory mechanisms are discussed including novel areas of therapeutic intervention. Restoring homeostasis to these dysregulated healing responses, or simply neutralizing the key pro-fibrotic mediators may prevent or slow the progression of pulmonary fibrosis.

Figure 1

Phases of wound healing. A three-phase injury and wound-healing model describes distinct phases of a successful response. (1) Injury; many agents can cause pulmonary injury, including environmental particles, allergens, infectious agents, chemotherapy and radiation. Disruption of epithelial and endothelial cells initiate an anti-fibrinolytic cascade, temporarily plugging the affected tissue. (2) Inflammation; circulating inflammatory cells and fibrocytes are recruited to the injured site through chemokine gradients, supplying fibroblast-activating cytokines and growth factors. Neo-vascularization provides access to damaged areas and a steady stream of inflammatory, anti-inflammatory, and phagocytic cells. (3) Fibroblasts contract and decrease the size of the wound. Inflammatory cells and α-SMA+ myofibroblasts undergo apoptosis, terminating collagen deposition, and are cleared by phagocytic cells. Epithelial and endothelial cells are replaced and tissue architecture is restored. PowerPoint slide

Figure 2

Imbalanced wound-healing response. For successful wound healing, a regulated response is maintained through negative feedback loops and a balance of catabolising and regenerative processes. Several imbalances may develop and lead a normal healing response into a fibrotic cascade. Excessive inflammation and the production of inflammatory and fibroblast-activating cytokines, through a breakdown in anti-inflammatory mechanisms can develop. Over-production of angiogenic CXC ELR⁺ chemokines, the recruitment of fibrocytes and increased frequency of α-SMA+ cells in the injury site can result in too much collagen deposition. Resetting the balance with targeted therapeutics (i.e., cytokine-blocking antibodies) may help slow the progression of fibrosis. PowerPoint slide