Review ArticleOxidative stress, extracellular matrix targets, and idiopathic pulmonary fibrosis
Introduction
The lung is continually exposed to higher oxygen levels than other tissues. Furthermore, exogenous oxidants, as well as pollutants, can augment oxidant production and activate inflammatory cells to generate additional reactive oxygen and nitrogen species. The lung protects itself against these oxidants with protective antioxidants and antioxidant enzymes. Various disease states in the lung involve dysregulation of this balance through excessive oxidant production or decreases in antioxidants. Idiopathic pulmonary fibrosis (IPF) is a lung disease characterized by progressive fibrosis of the alveolar interstitium [1], [2]. Reactive oxygen species (ROS) and markers of oxidative stress are evident in human IPF [3], [4] and levels of ROS negatively correlate with pulmonary function in IPF and may predict disease severity [5].
Section snippets
Diagnosis and pathological findings
Idiopathic Pulmonary Fibrosis is an interstitial lung disease characterized by severe and progressive fibrosis of the alveolar interstitium. In the United States, the prevalence of IPF is estimated to be 42.7 per 100,000 and the disease incidence to be 16.3 per 100,000 [6]. Patients develop symptoms of dyspnea (shortness of breath) and nonproductive cough with presentation between 50 and 70 years of age. IPF is slightly more common in males than females [2] and has a dismal prognosis with a
Oxidative Stress in the Lung
Oxidative stress is frequently defined as the imbalance of oxidant production and antioxidant defenses, where oxidants dominate and lead to cellular dysfunction and tissue damage. When considering oxidative stress, the lung is somewhat unique due to its exposure to relatively higher oxygen tensions than other tissues. The oxygen pressure of inhaled air is 20 kPa (150 mm Hg). Pressures in venous blood flow are around 6 kPa (45 mm Hg) and may be as low as 0.13 kPa in some tissues, while the oxygen
Oxidative Stress and IPF—Evidence from Patient Populations
The underlying pathogenesis of pulmonary fibrosis is currently thought to involve the presence of a persistent stimuli or injury, such as oxidative stress, and dysregulated repair of the lung that results in fibrosis. Several studies have found evidence of increased oxidative stress in idiopathic pulmonary fibrosis. Reduction–oxidation products and free radicals of oxygen metabolism are difficult to measure directly in tissues; thus many clinical studies have utilized biological markers of
Therapeutic Approaches—Controlling Oxidative Stress and Treatment
Despite recent studies and advances in the understanding of the pathogenesis and clinical course, there are currently no effective therapies for IPF, aside from lung transplantation, which comes with its own complications. Several options are available, such as anti-inflammatory agents; however, there are very few to no clinical studies that show improvements in progression-free survival, functional capacity, or quality of life [175]. While corticosteroids have been used over the last 50 years,
Final Discussion
The current belief in IPF pathogenesis is that cellular injury, which is often repetitive, acts as the inciting event for fibrosis development and oxidative imbalance within the lung. Causes of the oxidative stress include, but are not limited to, the cellular injury, transition metal exposure, inflammation, or drugs that participate in reduction–oxidation reactions. The importance of oxidative modifications to the extracellular matrix and how this alters cellular responses in human IPF remain
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