What We Know About the Pathogenesis of Idiopathic Pulmonary Fibrosis

S. Puglisi, MD; S. E. Torrisi, MD; R. Giuliano, MD; V. Vindigni, MD; C. Vancheri, MD, PhD

Disclosures

Semin Respir Crit Care Med. 2016;37(3):358-367. 

In This Article

Abstract and Introduction

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease of unknown cause, occurring in adults, limited to the lungs and associated with the pathologic and radiologic pattern of usual interstitial pneumonia. Prognosis is poor, and most patients die of respiratory failure within 3 to 6 years from the onset of symptoms. Although our understanding of the pathogenesis of IPF has improved over the past two decades, the mechanisms responsible for this disorder have not been clearly defined. Aging is the single most important risk factor, but genetic, environmental, and diverse exogenous factors such as smoking, viral infections, chronic tissue injury (i.e., gastroesophageal reflux disease, traction injury) play contributory roles. In this review, we focus on pathogenetic mechanisms that we think are crucial for the initiation of the fibrotic process and for its progressive evolution. In the early stage of the disease, in the context of the permissive genetic background combined with the presence of specific risk factors, alveolar epithelial cells play a leading role. Subsequent evolution of the fibrotic process and its lethal progression is likely due to the abnormal tissue repair process that takes place in the lung and to the inability to counteract this process. In this phase of the disease, fibroblasts assume a crucial role. Current pharmacological treatment strategies for IPF have only modest value, principally by slowing the course of disease progression. Unfortunately, improvement or cure has not yet been achieved with pharmacological agents. The challenge for the future is to improve the comprehension of the mechanisms involved in the inception and evolution of IPF and their articulated interactions. This is fundamental not only to conceive and develop new drugs against this dreadful disease but also to apply different therapeutic approaches such as drug repositioning and personalized therapies in the management of IPF.

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease of unknown cause, occurring in adults, limited to the lungs and associated with pathologic and radiologic pattern of usual interstitial pneumonia.[1] IPF is characterized by severe morphofunctional changes of the alveolar architecture, resulting in progressive dyspnea and lung failure. In spite of the undeniable progress in our understanding of the pathogenesis of IPF and the different hypotheses that have been postulated over the years, the true nature of this disease still remains, in large part, unknown. Most of the information gathered in the past 20 years derives either from diagnostic lung biopsies or from explanted lungs. In both cases, these tissues are the expression of one specific moment in the disease process; they are single photographs in a long and articulated movie, full of actors, in which it is very difficult to understand who plays a supporting or a leading role. In addition, lung tissue from biopsy and even explanted lung are generally studied when the disease is already clinically evident, in an advanced stage, when the initial and crucial pathogenic events initiating the disease have faded. The other important sources of information are in vivo and in vitro models of lung fibrosis. The bleomycin model of lung fibrosis is widely used, and certainly has given an important contribution to the understanding of some aspects of lung fibrosis.[2] Nevertheless, there is agreement in the scientific literature on the inadequacy of this model and considering it the "less worse" animal model in mimicking human lung fibrosis.[3] In vitro experiments are certainly important and very appealing, but at the same time with obvious limitations and with the need to confirm their findings in vivo, either in animals or humans. In spite of these objective difficulties in clarifying the pathogenesis, IPF can be considered the result of the interaction between the individual genetic background and the insult of various exogenous factors such as smoking, viral infections, chronic tissue injury (i.e., gastroesophageal reflux disease [GERD], traction injury), as well as environmental or professional exposure. In this context, aging plays an additional role as an endogenous risk factor. Genomic instability, epigenetic mutations, telomere attrition, cellular senescence, as well as other alterations, facilitated by the aging process, may affect the behavior of lung cells altering their normal response to chronic damage.[4]

Based on these considerations, we will try to focus this review on some aspects of IPF pathogenesis that we think are crucial for the initiation of the fibrotic process and for its progressive evolution. In the early stage of the disease, in the context of the permissive genetic background combined with the presence of specific risk factors, alveolar epithelial cells (AECs) play a leading role. Subsequent evolution of the fibrotic process and its lethal progression is likely due to the abnormal tissue repair process that takes place in the lung, and to the inability to counteract this process. In this phase of the disease, fibroblasts assume a crucial role.

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