Context.—Idiopathic pulmonary fibrosis is a progressive, fatal lung disease occurring in older individuals. Despite 50 years of accrued data about the disease, little progress has been made in slowing functional loss or in decreasing patient mortality.

Objective.—To present a novel hypothesis on the etiology and pathogenesis of idiopathic pulmonary fibrosis.

Design.—Published data are reviewed regarding the epidemiology, clinical presentation, natural history, radiologic findings, and pathologic findings in patients with idiopathic pulmonary fibrosis.

Results.—Patients with idiopathic pulmonary fibrosis may be predisposed genetically to tractional injury to the peripheral lung. The result is recurrent damage to the epithelial-mesenchymal interface, preferentially at the outer edges of the basilar lung lobules where tractional stress is high during inspiration, compliance is relatively low, and there is a greater tendency for alveolar collapse at end-expiration. A distinctive “reticular network of injury” (the fibroblast focus) forms, attended by a prolonged phase of wound repair (tear and slow repair). Discrete areas of alveolar collapse are observed in scar at the periphery of the lung lobules. The cycle repeats over many years resulting in progressive fibrous remodeling and replacement of the alveoli in a lobule by bronchiolar cysts surrounded by scar (honeycomb lung). Abnormalities in surfactant function are proposed as a potential mechanism of initial lung damage. Age of onset may be a function of a required threshold of environmental exposures (eg, cigarette smoking) or other comorbid injury to the aging lung.

Conclusions.—Evidence supporting this hypothesis is presented and potential mechanisms are discussed. A potential role for contributing cofactors is presented.

Idiopathic pulmonary fibrosis (IPF) is a specific form of progressive, fibrosing interstitial pneumonia of unknown etiology, occurring most frequently in older men, and confined to the lungs.1,2 The prognosis historically for patients with IPF rivals that of many forms of cancer, with median survival estimates at less than 3.5 years from diagnosis. Clinical trials of potential treatments have failed to affect the progression of disease or the survival in patients with IPF, despite substantial advances in immunomodulatory and antifibrotic therapies.3 

Most human diseases that are characterized by slowly progressive tissue fibrosis have underpinnings in pathologic inflammatory reactions. The best-known examples of these are the rheumatic autoimmune diseases, where tissue damage is mediated by immune dysfunction directed at self-antigens.4 These diseases have served as excellent models for understanding immune system disorders and for designing effective anti-inflammatory treatment strategies. For patients with IPF, decades of empiric immunosuppressive therapy and more than 20 years of clinical trials with immunosuppressive and antifibrotic agents have led to the now widely held conclusion that IPF is not inherently an inflammatory disease, in contrast to previous assertions.5 Moreover, the established fibrosis that occurs in IPF does not appear to be reversible using any therapies tested thus far.2,6 

Current lines of research in IPF are focused on the molecular genetics of pathologic events likely occurring at the epithelial-mesenchymal interface of the alveolus.712 Based on data derived from the study of samples from patients with IPF and in vitro laboratory investigations, researchers have concluded that IPF may be mediated by shortened survival of lung epithelial cells,10 prolonged survival of myofibroblasts activated by unknown injury, or both.11 None of the approaches have attempted to reconcile the complete body of evidence regarding the known clinical, radiologic, and histopathologic aspects of the disease. With an abundance of sophisticated laboratory methodology available, it is easy to lose sight of the data accrued on patients with IPF from decades of study. In the pages that follow, the key observational data related to IPF are presented, and from these, a working hypothesis on the etiology and pathogenesis is proposed (Figure 1). A role for contributing cofactors is discussed.

Figure 1.

Essential data to be incorporated in a hypothesis on etiology and pathogenesis of idiopathic pulmonary fibrosis (IPF).

Figure 1.

Essential data to be incorporated in a hypothesis on etiology and pathogenesis of idiopathic pulmonary fibrosis (IPF).

EPIDEMIOLOGY OF IPF

At the beginning of the past century, pathologists encountered a diffuse lung disease in postmortem examinations, where the lungs were shrunken, cystic, and accompanied by fibrosis (so-called honeycomb fibrosis or simply honeycomb lung) (Figure 2, A and B). In time, this honeycomb remodeling was discovered to occur as a result of many different types of injury, but the mechanisms for that fibrosis remained elusive.13,14 

Figure 2.

Gross honeycomb lung. A, Paper-thin Gough-Wentworth section of whole lung from a patient with idiopathic pulmonary fibrosis (IPF). Note the near-total replacement of the lower lobe by honeycomb cysts and relative sparing in the upper lobe (Courtesy of the Charles B. Carrington, MD, Memorial Lung Pathology Collection—received originally from Jethro Gough, MD). B, Gross autopsy lung from a patient with IPF showing rigid, distended subpleural cysts surrounded by fibrotic lung. Reprinted with permission from Practical Pulmonary Pathology: A Diagnostic Approach. Leslie KO, Wick MR, eds; 2nd ed., page 219; by Elsevier, copyright 2011.

Figure 3. Comparison of high-resolution computed axial tomography (HRCT) and gross lung honeycomb patterns. A, This HRCT demonstrates the characteristic features of usual interstitial pneumonia (UIP). Note the asymmetry of peripheral honeycomb cysts (image courtesy of Richard Webb, MD). B, Gross pathology of advanced honeycomb fibrosis in UIP. The confluent honeycomb cysts form a band under the pleura and extend into the lung along interlobular septa.

Figure 4. Usual interstitial pneumonia. A, At very low magnification, a ringlike pattern of peripheral lobular scarring with central preserved lung distorted by traction emphysema. B, Another patient with idiopathic pulmonary fibrosis, showing the variable involvement of lobules by fibrosis and microscopic honeycombing. C, The fibroblast focus (asterisk), which usually appears as shown in this tissue section: a “bulge” of immature fibroblasts in pale, myxoid stroma, covered by a layer of reactive type 2 cells, variable chronic inflammation, with dense fibrosis beneath. The dilated veins at the bottom of the figure are in pleura in this photograph (pv) (hematoxylin-eosin, original magnifications ×12.5 [A and B] and ×200 [C]).

Figure 2.

Gross honeycomb lung. A, Paper-thin Gough-Wentworth section of whole lung from a patient with idiopathic pulmonary fibrosis (IPF). Note the near-total replacement of the lower lobe by honeycomb cysts and relative sparing in the upper lobe (Courtesy of the Charles B. Carrington, MD, Memorial Lung Pathology Collection—received originally from Jethro Gough, MD). B, Gross autopsy lung from a patient with IPF showing rigid, distended subpleural cysts surrounded by fibrotic lung. Reprinted with permission from Practical Pulmonary Pathology: A Diagnostic Approach. Leslie KO, Wick MR, eds; 2nd ed., page 219; by Elsevier, copyright 2011.

Figure 3. Comparison of high-resolution computed axial tomography (HRCT) and gross lung honeycomb patterns. A, This HRCT demonstrates the characteristic features of usual interstitial pneumonia (UIP). Note the asymmetry of peripheral honeycomb cysts (image courtesy of Richard Webb, MD). B, Gross pathology of advanced honeycomb fibrosis in UIP. The confluent honeycomb cysts form a band under the pleura and extend into the lung along interlobular septa.

Figure 4. Usual interstitial pneumonia. A, At very low magnification, a ringlike pattern of peripheral lobular scarring with central preserved lung distorted by traction emphysema. B, Another patient with idiopathic pulmonary fibrosis, showing the variable involvement of lobules by fibrosis and microscopic honeycombing. C, The fibroblast focus (asterisk), which usually appears as shown in this tissue section: a “bulge” of immature fibroblasts in pale, myxoid stroma, covered by a layer of reactive type 2 cells, variable chronic inflammation, with dense fibrosis beneath. The dilated veins at the bottom of the figure are in pleura in this photograph (pv) (hematoxylin-eosin, original magnifications ×12.5 [A and B] and ×200 [C]).

We now recognize an idiopathic form of chronic, progressive, fibrosing interstitial pneumonia occurring primarily in adults and refer to it clinically as IPF. Idiopathic pulmonary fibrosis is a relentlessly progressive disease of older individuals, limited to the lungs, and associated with cigarette smoking, frequent history of dust and other environmental exposures, and ultimately, honeycomb transformation of the lungs. There is a male predominance and an estimated annual incidence of 30 000 in the United States, with a prevalence of 80 000.2,15 The true incidence and prevalence in other countries remains unknown and few population-based studies are available.16 The mortality data from previous studies suggest a median survival following diagnosis of 3.2 years, rivaling many forms of cancer. A familial form of unexplained lung fibrosis is described but occurs much less frequently and affects slightly younger patients.1723 Key questions that arise regarding the epidemiology of IPF are presented in Table 1.

Table 1. 

Key Questions Regarding the Epidemiology of Idiopathic Pulmonary Fibrosis (IPF)

Key Questions Regarding the Epidemiology of Idiopathic Pulmonary Fibrosis (IPF)
Key Questions Regarding the Epidemiology of Idiopathic Pulmonary Fibrosis (IPF)

CLINICAL FEATURES AND NATURAL HISTORY OF IPF

Patients with IPF are typically older than 50 years at the time of their clinical presentation, although the age distribution, at presentation, is quite wide.1 Slowly progressive breathlessness, especially with exertion, is the most common clinical complaint. Nonproductive cough is typically present and can be a difficult component of the disease to manage. Laboratory studies may show mild nonspecific elevation of antinuclear antibodies, but serology diagnostic of defined rheumatic disease is, by definition, absent. Pulmonary function testing most consistently reveals restrictive physiology, with decreased total lung capacity, forced vital capacity, and diffusing capacity for carbon monoxide. Oxygen desaturation with exercise is commonly present and the degree of desaturation during the 6-minute walk test has been shown to have prognostic value for the individual patient.24 Patients with IPF suffer progressive decline in pulmonary function over the course of their illness. Functional decline may be episodic and unpredictable, with long periods of apparent stability expected. With each decline, patients may stabilize but never experience improvement in measured function.1,2 

CLINICAL, ACUTE EXACERBATIONS OF IPF

Idiopathic pulmonary fibrosis seems to have 2 patterns of decline in lung function; one being slow and insidious and the other being episodic and more severe. When an episode of decline progresses with sufficient rapidness to demand clinical attention, the term acute exacerbation of IPF has been applied.25 The causes of acute exacerbations remain unknown, despite ample hypotheses as to etiology, clinical predictors of outcome, and potential mechanisms of injury.2629 Infection seems not to be a common initiating factor.30 A recent study suggested subclinical aspiration as a plausible cause, based on right-left asymmetry of the exacerbation on imaging correlated to the patient's preferred side for sleeping.31 Key questions related to risk factors and clinical manifestations of IPF are presented in Table 2.

Table 2. 

Key Questions Regarding the Clinical Presentation and Characteristics of Idiopathic Pulmonary Fibrosis (IPF)

Key Questions Regarding the Clinical Presentation and Characteristics of Idiopathic Pulmonary Fibrosis (IPF)
Key Questions Regarding the Clinical Presentation and Characteristics of Idiopathic Pulmonary Fibrosis (IPF)

IMAGING STUDIES OF IPF

With the advent of high-resolution computed axial tomography (HRCT), a consistent picture of IPF has emerged.2 This is a disease of the basal and peripheral lungs that progresses centrally and toward the lung apices over time. The characteristic appearance is that of patchy, coarse, subpleural reticulation; distortion of lung architecture; and the presence of pleural-based cysts, a required feature for a confident diagnosis of what thoracic radiologists refer to as usual interstitial pneumonia” (UIP).32 The term UIP is not a radiologic term but a histopathologic one, first coined by Averill Liebow33 in his original description of the pathology of the “usual” and most common form of lung fibrosis occurring in adults (discussed below). On HRCT, subpleural disease is variable in distribution along the pleura, with skip areas occurring frequently (“broken sawtooth pattern” according to M. Maffessanti, MD, and G. Dalpiaz, MD, oral communication, 2009) and some asymmetry from side to side expected. When subpleural honeycombing is identified at the bases, increased reticular lines are nearly always present in the upper lung zones.2 A gradient toward the apex occurs, with abnormalities accruing from base toward the apex as the disease progresses.

Today, a characteristic HRCT in the appropriate clinical and physiologic setting obviates the need for a surgical lung biopsy in most practice settings (Figure 3, A and B). When IPF is a clinical concern, a less-than-diagnostic HRCT scan may be overridden by a diagnostic surgical lung biopsy (ie, UIP histopathology precedes UIP radiology).34 Key questions that must be addressed regarding the radiologic characteristics of IPF are presented in Table 3.

Table 3. 

Key Questions Regarding the Radiologic Features of Idiopathic Pulmonary Fibrosis (IPF)

Key Questions Regarding the Radiologic Features of Idiopathic Pulmonary Fibrosis (IPF)
Key Questions Regarding the Radiologic Features of Idiopathic Pulmonary Fibrosis (IPF)

HISTOPATHOLOGY OF IPF

Before the common availability of the surgical lung biopsy and lobar resections for lung diseases, the histopathologic attributes of IPF in its earlier stages were unknown. Liebow33 was the first to describe a pattern of lung fibrosis in biopsies and autopsy lungs that he recognized as the usual (ie, most common) form of lung fibrosis. For Liebow, this UIP was heterogeneous in causation, with roughly half of cases being idiopathic. We now recognize UIP as the histopathologic manifestation of IPF.2,35 Unfortunately, decades of confusion have accumulated regarding the histopathology of UIP, both for pulmonologists and for pathologists alike.

In patients with clinical and radiologic IPF, UIP is a distinctive and highly recognizable pattern of lung fibrosis. However, when trying to establish a histopathologic diagnosis of UIP, many different forms of advanced lung fibrosis tend to be lumped together and called UIP. Usual interstitial pneumonia in IPF has a distinctive histopathologic appearance, with a “patchwork” pattern of scar formation alternating with zones of normal lung in the biopsy, referred to as temporal heterogeneity.35,36 In this formation, fibroblast foci (FF) exist at the interface between fibrosis and uninvolved lung, and microscopic honeycombing is nearly always present, in the classic example, even when the burden of fibrosis in the biopsy seems small (Figure 4, A through C).

Currently we recognize that a UIP pattern of disease can occur in other conditions, such as in some patients with rheumatoid arthritis37 and chronic hypersensitivity pneumonitis,38 but when this occurs, the fidelity of the UIP pattern often is not as robust as that seen in IPF (eg, more inflammation, less peripheral lobular distribution, more airway-centered inflammation and scarring). A patchwork of scar seems to result in these diseases as a late manifestation of airway-centered scarring where fibrosis extends from the center of lobules to their periphery.

In patients with IPF, UIP histopathology in lung specimens recapitulates the patchy, peripheral lobar distribution seen on HRCT distribution. Under the microscope, coarse, peripheral, lobular fibrosis is characteristic. Partially or completely scarred lobules, devoid of alveolar spaces, are present. In this scar tissue, small cysts lined by respiratory epithelium are seen, surrounded by airway smooth muscle. These microcysts are connected to the more-proximal airways and, with continued respiration, form into larger cysts. These are the presumptive precursors to the macroscopic cysts visible on imaging (Figure 5).

Figure 5.

Histopathology of advanced lung remodeling in idiopathic pulmonary fibrosis (IPF). The lung lobules are outlined (dashed lines) to emphasize the residual lobular architecture in the advanced remodeling of IPF. This final stage of alveolar destruction causes a diminution of the lobular size and an overall decrease in lung volume. Note the residual pulmonary arteries (A) and bronchioles (br). A few dilated alveolar ducts remain but the alveoli are conspicuously absent (hematoxylin-eosin, original magnification ×12.5).

Figure 6. Two-dimensional (2D) versus 3-dimensional (3D) representations of fibroblast foci (ff). A, The ff in 2D tissue sections has been shown in 3D reconstruction to be a reticulum of interconnected repair, similar to the cracks that form in a dry river bed (hematoxylin-eosin, original magnification ×200 [A]). B, Photograph of dry river bed, courtesy of photographer Peter Pallagi, Gilbert, Arizona (no copyright).

Figure 5.

Histopathology of advanced lung remodeling in idiopathic pulmonary fibrosis (IPF). The lung lobules are outlined (dashed lines) to emphasize the residual lobular architecture in the advanced remodeling of IPF. This final stage of alveolar destruction causes a diminution of the lobular size and an overall decrease in lung volume. Note the residual pulmonary arteries (A) and bronchioles (br). A few dilated alveolar ducts remain but the alveoli are conspicuously absent (hematoxylin-eosin, original magnification ×12.5).

Figure 6. Two-dimensional (2D) versus 3-dimensional (3D) representations of fibroblast foci (ff). A, The ff in 2D tissue sections has been shown in 3D reconstruction to be a reticulum of interconnected repair, similar to the cracks that form in a dry river bed (hematoxylin-eosin, original magnification ×200 [A]). B, Photograph of dry river bed, courtesy of photographer Peter Pallagi, Gilbert, Arizona (no copyright).

Another hallmark of UIP is the fibroblast focus, a microscopic patch of fibroblastic repair found in variable numbers at the edge of established scar. A recent 3-dimensional reconstruction study has shown that the fibroblast focus in UIP is not a discrete focus but an interconnected “reticulum of repair” (Figure 6, A and B).39 

The occurrence of similar structures in other forms of lung pathology suggests that these are lines of tractional injury to the epithelial-mesenchymal interface of the peripheral alveoli (Figure 7, A and B).

Figure 7.

Fibroblast foci in recurrent pneumothorax. Slides from a 22-year-old woman with recurrent pneumothorax that required surgical intervention to repair. A, At very low magnification, thick areas of subpleural fibrosis extend into the underlying lung. B, At higher magnification, fibroblast foci (ff) are seen at the edge of scar (hematoxylin-eosin, original magnifications ×12.5 [A] and ×200 [B]).

Figure 8. Alveolar collapse in idiopathic pulmonary fibrosis (IPF) demonstrated by elastic tissue stains. A, The established fibrosis surrounding microscopic honeycomb (mh) cysts is laced with coiled and convoluted elastic tissue fibers suggesting alveolar collapse in collagen (staining eosinophilic). B, At higher magnification, abundant black elastic tissue fibers speak to condensation of normal alveolar elastic tissue embedded in pink collagen fibers (Movat pentachrome, original magnifications ×12.5 [A] and ×200 [B]).

Figure 7.

Fibroblast foci in recurrent pneumothorax. Slides from a 22-year-old woman with recurrent pneumothorax that required surgical intervention to repair. A, At very low magnification, thick areas of subpleural fibrosis extend into the underlying lung. B, At higher magnification, fibroblast foci (ff) are seen at the edge of scar (hematoxylin-eosin, original magnifications ×12.5 [A] and ×200 [B]).

Figure 8. Alveolar collapse in idiopathic pulmonary fibrosis (IPF) demonstrated by elastic tissue stains. A, The established fibrosis surrounding microscopic honeycomb (mh) cysts is laced with coiled and convoluted elastic tissue fibers suggesting alveolar collapse in collagen (staining eosinophilic). B, At higher magnification, abundant black elastic tissue fibers speak to condensation of normal alveolar elastic tissue embedded in pink collagen fibers (Movat pentachrome, original magnifications ×12.5 [A] and ×200 [B]).

In all lung biopsies of UIP, the FF have a very similar appearance in 2-dimensional sections, which is remarkable unless they all form at the same time (days before biopsy), or they exist for prolonged periods as immature fibroblastic “plugs” without complete resolution. If this were not the case, one would expect to see progressively less cellular and collagenized FF in any given lung biopsy specimen as a natural part of the well-documented 10 to 14 day natural cycle of wound repair. Key questions that arise from the pathology of UIP in IPF are presented in Table 4.

Table 4. 

Key Questions Regarding the Gross and Microscopic Features of Idiopathic Pulmonary Fibrosis (IPF)

Key Questions Regarding the Gross and Microscopic Features of Idiopathic Pulmonary Fibrosis (IPF)
Key Questions Regarding the Gross and Microscopic Features of Idiopathic Pulmonary Fibrosis (IPF)

NEED FOR A UNIFYING HYPOTHESIS

The clinical, radiologic, and histopathologic observations in IPF present a distinctive and possibly unique picture. These demand our attention and must be accounted for as we move forward in our exploration and eventual understanding of this disease. Based on this body of evidence, a unifying hypothesis for the etiology and pathogenesis of IPF is proposed.

HYPOTHESIS

Idiopathic pulmonary fibrosis is a disease of recurrent stretch injury to the peripheral and basal lung occurring over many years in predisposed individuals. The tractional forces related to respiration are highest in the areas where disease appears first on chest imaging and in pathologic examination, corresponding to regions prone to physiologic alveolar collapse at rest. Inherited or acquired abnormalities in surfactant function likely play a role, given this lipoprotein's unique role in reducing tractional injury related to alveolar collapse and rapid reopening during respiration.

Some Key Observations Addressed by This Hypothesis

IPF Is a Disease of Older Adults

The actual age of onset and speed of progression could be influenced by the type and amount of exposure accrued during a patient's lifetime. Most patients with IPF are prior cigarette smokers or report other inhalational exposures. Factors other than inhalational injury may also be at play, such as autoimmune inflammatory disease. The patient predisposed to develop IPF may have their disease modified by such events (eg, UIP in asbestos is IPF with asbestos exposure, UIP in rheumatoid arthritis is IPF modified by rheumatoid lung disease, etc). This idea is appealing because UIP pattern fibrosis is not the common manifestation of any of these diseases in the lung. Logically, if surfactant abnormalities are genetically programmed in patients with IPF, any defect would need to be sublethal and possibly activated or exacerbated later in life to explain the observed onset of clinical disease.

IPF Produces Peripheral and Bibasilar Abnormalities on HRCT

The posterior lung bases are a region naturally predisposed to alveolar collapse at rest. When the alveoli are pulled open by the actions of the chest wall and diaphragm, mechanical forces are high at the pleural surface, and these must be transmitted to the deeper lobules rapidly and efficiently.40,41 In the patient with IPF, a combination of mechanical stress in the periphery and an increased tendency for alveolar collapse in the same regions occurs. These factors act together to cause lines of shear stress and fracture of the epithelial-mesenchymal interface because collapsed alveoli are suddenly pulled open during inspiration. The notion of alveolar collapse in IPF is not new. Myers and Katzenstein42 demonstrated ultrastructurally that foci of epithelial necrosis occur in UIP attended by complex alveolar infolding consistent with collapsed alveolar walls (see further discussion below in “Microscopic Honeycombing Is a Marker for Complete Alveolar Destruction of a Lobule”). Later, Galvin and Franks43 reviewed the distribution conundrum of IPF in an excellent radiologic-histopathologic analysis of IPF and supported the notion of alveolar collapse in IPF. In their 2010 article they wrote43 (p697): “Structures with a smaller radius of curvature and subsequent increased surface tension are unstable and thus more likely to collapse. Once initiated, the process, powered by the increasing disparity between the enlarging alveolar ducts and the collapsing small alveoli that surround them, is more likely to continue.”

This alveolar-collapse model would also help explain the tendency for disease to accrue microscopically at the periphery of lung lobules in UIP, given similar mechanical requirements during inhalation for transmission of outward force along a gradient from the periphery toward the lobule center.40 

Without an animal model of the disease, we can only speculate on the exact sequence of events involved. How the formation of a reticulum of stretch injury in the peripheral lung (and peripheral edges of the lobules within) leads to persistent alveolar collapse is not clear from any available data and remains the missing piece to the puzzle. We can appreciate the steps before and after collapse in static lung tissue sections, but not the act of collapse. The presence of a complex elastic tissue matrix in fibrotic areas of UIP suggests the elastic fibers of collapsed alveolar walls and provides visual support for that being the mechanism of alveolar attrition in the disease (as opposed to destruction by dissolution) (Figure 8, A and B).

Another consequence of lobular alveolar collapse and scar formation at the edges of the lung lobules may be reflected in the greater-than-expected incidence of pulmonary hypertension in IPF44,45 and the peculiar observation that pleural effusions rarely (if ever) occur in patients who have been diagnosed with IPF (R. Webb, MD, oral communication, 2007). The progressive collapse of peripheral lobular alveoli in scar may ultimately slow or impede the passage of venous blood and interstitial fluid into collecting channels of the interlobular septa and across the visceral pleura. This “blockage” in IPF appears to be effective even under the increased hydrostatic pressure produced by heart failure.

Surfactant Abnormalities Have Been Identified in IPF Patients

Ample data exist regarding lavage and serum surfactant abnormalities in IPF, but those studies have, until now, lacked a mechanism to explain how such abnormalities might initiate or contribute to disease pathogenesis.4656 Surfactant is implicated in the pathogenesis of IPF for several reasons. First, it is unique to the lung (like IPF). Surfactant plays a critical role in preventing alveolar collapse at end-expiration and reduces alveolar surface tension during inspiration, thereby, increasing the mechanical efficiency of respiration.57 Less than complete failure in these 2 functions might be survivable into adult life. Second, premature infants deficient in surfactant develop diffuse alveolar damage early after beginning respiration.58 This likely occurs from global alveolar trauma related to high alveolar surface tension during inspiration, but a role for an alternate consequence of surfactant deficiency in this setting is difficult to discount. Third, the natural properties of this lipoprotein are highly complex and affect alveolar health on several levels, including defense.59 Fourth, heritable forms of surfactant dysfunction have been reported to produce interstitial lung disease and possibly UIP in a subset of patients with familial idiopathic interstitial pneumonia.17,60 The specifics of this surfactant dysfunction are unknown in IPF but may be similar in mechanism to the recognized forms of inherited lung disease related to aberrations of surfactant.23,59,60 

A Reticulum of FF Occurs at the Periphery of the Lung Lobules in IPF

In IPF, FF occur most consistently in direct apposition to the scarred matrix because they exist as a marker for stress fracture to the epithelial-mesenchymal interface at the alveolar surface (Figure 9, A and B). Fibroblast foci can be observed in other lung diseases, most often where shear stress is known to occur. The best example of this was demonstrated earlier (Figure 7, B) in the otherwise healthy young individual who developed recurrent spontaneous pneumothorax. The 3-dimensional configuration of FF in non-IPF settings remains to be discovered. An unexplained peculiarity of FF in UIP, and in other conditions where they can be observed, is their remarkably consistent appearance under the microscope. This peculiarity might not be immediately intuitive. The lack of transitional lesions reflecting later events in wound repair is remarkable and likely speaks to some degree of disordered wound repair at these sites.61 Alternatively, the constant motion created by respiration may create in the lung a unique setting for wound repair. Organizing pneumonia provides a more common (but morphologically different) pathway for repair in the lung with the formation of fibroblastic polyps within alveolar spaces and terminal airways. Although FF are distinctive in UIP, the possibility that they might be an epiphenomenon simply related to fibrosis and tractional stress cannot be completely discounted.

Figure 9.

Lung architecture at the periphery and proposed mechanism of stretch injury. A, Schematic drawing of the superficial and deep lobules of the lung. The structural relationships between the superficial and deep lung lobules are important in the mechanics of lung ventilation (Modified from Nagaishi C. Functional Anatomy and Histology of the Lung: Fig. 45. Baltimore, MD, and London, England: University Park Press; 1972:28). B, The hypothesis proposed implicates shear forces in the peripheral lung that lead to tears in the epithelium, followed by prolonged fibroblastic repair.

Figure 10. Conceptualized process by which lung lobules become foci of microscopic honeycombing. This histopathologic manifestation of advanced lung remodeling with microcyst formation seems to precede the radiologic finding of honeycomb cysts by an undefined period. The alveoli (al) in the involved lobules (A) become obliterated in scar, and the terminal ends of the respiratory bronchioles and alveolar ducts expand to form (B) aggregations of mucous-filled cysts (C).

Figure 9.

Lung architecture at the periphery and proposed mechanism of stretch injury. A, Schematic drawing of the superficial and deep lobules of the lung. The structural relationships between the superficial and deep lung lobules are important in the mechanics of lung ventilation (Modified from Nagaishi C. Functional Anatomy and Histology of the Lung: Fig. 45. Baltimore, MD, and London, England: University Park Press; 1972:28). B, The hypothesis proposed implicates shear forces in the peripheral lung that lead to tears in the epithelium, followed by prolonged fibroblastic repair.

Figure 10. Conceptualized process by which lung lobules become foci of microscopic honeycombing. This histopathologic manifestation of advanced lung remodeling with microcyst formation seems to precede the radiologic finding of honeycomb cysts by an undefined period. The alveoli (al) in the involved lobules (A) become obliterated in scar, and the terminal ends of the respiratory bronchioles and alveolar ducts expand to form (B) aggregations of mucous-filled cysts (C).

Microscopic Honeycombing Is a Marker for Complete Alveolar Destruction of a Lobule

The idea that honeycomb remodeling results from dilation of the small intralobular airways is not new.13,14 Rudimentary 3-dimensional reconstruction of honeycomb lungs, more than 40 years ago, suggested this mechanism. Also, the lining of microscopic honeycomb cysts in IPF is, in fact, airway respiratory mucosa, and the walls of these cysts resemble the smooth muscle of the terminal airway. In the advanced fibrosis in IPF, the only components missing are the alveolar spaces. Entire regions of the peripheral lung are composed entirely of closely apposed respiratory bronchioles and pulmonary arteries, embedded in a fibrous matrix replete with elastic tissue, resembling collapsed and fused alveolar walls. Once the alveoli in a lobule have fully collapsed and become incorporated into the scar, continued respiratory motion presumably causes progressive dilatation of the residual respiratory bronchioles until grossly (and radiologically) visible cysts form (Figure 10, A and B). Microscopic honeycombing appears to precede radiologic honeycombing by a yet to be defined period (likely, many years, based on anecdotal observations and limited retrospective studies).

Gastroesophageal Reflux Disease and Occult Microaspiration in IPF

Gastroesophageal reflux disease is common in patients with IPF, although it is often discounted as a secondary consequence of lung fibrosis with resultant increased pressure gradients across the diaphragm. As early as 1998, Tobin and colleagues62 described a high incidence of gastroesophageal reflux disease in patients with IPF and proposed a role for it in the pathogenesis of the disease. Although it seems reasonable to assign an important potential role for microaspiration in the pathogenesis of acute exacerbation (see below), a primary etiologic role for reflux in all patients with IPF remains to be proven. Treatment of reflux has been shown to improve survival in patients with IPF.63 

Acute Exacerbation of IPF

Acute exacerbation of IPF may occur as a direct consequence of relatively rapid increases in mechanical stress acting on areas already modified by fibrous remodeling. Alternatively, acute exacerbation could be an independent injury not directly related to the underlying primary mechanism of disease. Acute exacerbation is rarely the initial presentation in IPF,64 and when this occurs, the background histopathology of UIP may be difficult to discern through the overlay of acute lung injury. Interestingly, it is not uncommon for patients newly diagnosed with IPF to recall a prior severe bout of “pneumonia” as the event that began their respiratory decline. Such events may represent early acute exacerbations. If acute exacerbations do occur at higher rates in preclinical disease, the injury must be less than global in the lung. Otherwise, the nearly normal lung parenchyma required for the diagnosis of UIP (“temporal heterogeneity”) would be absent in subsequent biopsies.

Conclusions

All scientific study begins with observation. In the absence of an animal model of IPF, a viable hypothesis regarding etiology and pathogenesis must reconcile a sizeable body of fundamental observations about the disease, accrued over decades of study. Without a unifying hypothesis, isolated molecular genetic and proteomic abnormalities gleaned from the patient with IPF must be viewed as data in search of context. Biomechanical forces involved in respiration may cause recurrent and progressive tractional injury to alveoli at the peripheral bases of the aging lung. This injury may occur as a function of an inherited genetic abnormality of surfactant. This molecule's unique role in reducing alveolar surface tension protects the alveolar parenchyma from tractional injury when areas of physiologic collapse are subjected to sudden opening. The stretch injury produces a reticular network of FF, which over time results in permanent alveolar collapse and piecemeal fibrous remodeling of affected lung lobules (Figure 11).

Figure 11.

Proposed pathogenetic sequence of events in idiopathic pulmonary fibrosis. The cycle may consist of (1) initial stretch injury to the epithelial-mesenchymal interface, with (2) formation of the fibroblastic reticulum. Type 2 cells proliferate over the tear in the lung and reconstitute the alveolar interface with air. (3) Localized persistent collapse of alveoli occurs from unknown mechanisms and is (4) attended by collagen deposition and (5) eventual vascular ingrowth. (6) The simplified lobules (or portions of lobules), devoid of alveoli, consist only of terminal airways. These dilate over time because of respiration and become (7) honeycomb lung. Reprinted with permission from Practical Pulmonary Pathology: A Diagnostic Approach. Leslie KO, Wick MR, eds; 2nd ed., page 219; by Elsevier, copyright 2011.

Figure 11.

Proposed pathogenetic sequence of events in idiopathic pulmonary fibrosis. The cycle may consist of (1) initial stretch injury to the epithelial-mesenchymal interface, with (2) formation of the fibroblastic reticulum. Type 2 cells proliferate over the tear in the lung and reconstitute the alveolar interface with air. (3) Localized persistent collapse of alveoli occurs from unknown mechanisms and is (4) attended by collagen deposition and (5) eventual vascular ingrowth. (6) The simplified lobules (or portions of lobules), devoid of alveoli, consist only of terminal airways. These dilate over time because of respiration and become (7) honeycomb lung. Reprinted with permission from Practical Pulmonary Pathology: A Diagnostic Approach. Leslie KO, Wick MR, eds; 2nd ed., page 219; by Elsevier, copyright 2011.

The earliest events in the process remain unclear, the pathobiology of the fibroblast focus in IPF and other diseases is still undefined, and the specific events that result in persistent alveolar collapse require further study. A hypothetic construct for integrating the results of laboratory investigations may finally help provide insight into this enigmatic and deadly disease.

References

1.
Costabel
U
,
King
TE
.
International consensus statement on idiopathic pulmonary fibrosis
.
Eur Respir J
.
2001
;
17
(
2
):
163
167
.
2.
Raghu
G
,
Collard
HR
,
Egan
JJ
, et al
;
for ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis
.
An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management
.
Am J Respir Crit Care Med
.
2011
;
183
(
6
):
788
824
.
3.
Klingsberg
RC
,
Mutsaers
SE
,
Lasky
JA
.
Current clinical trials for the treatment of idiopathic pulmonary fibrosis
.
Respirology
.
2010
;
15
(
1
):
19
31
.
4.
Nannini
C
,
Ryu
JH
,
Matteson
EL
.
Lung disease in rheumatoid arthritis
.
Curr Opin Rheumatol
.
2008
;
20
(
3
):
340
346
.
5.
Crystal
RG
,
Bitterman
PB
,
Mossman
B
, et al.
Future research directions in idiopathic pulmonary fibrosis: summary of a National Heart, Lung, and Blood Institute working group
.
Am J Respir Crit Care Med
.
2002
;
166
(
2
):
236
246
.
6.
Lasky
JA
,
Ortiz
LA
.
Antifibrotic therapy for the treatment of pulmonary fibrosis
.
Am J Med Sci
.
2001
;
322
(
4
):
213
221
.
7.
Chilosi
M
,
Doglioni
C
,
Murer
B
,
Poletti
V
.
Epithelial stem cell exhaustion in the pathogenesis of idiopathic pulmonary fibrosis
.
Sarcoidosis Vasc Diffuse Lung Dis
.
2010
;
27
(
1
):
7
18
.
8.
Ding
Q
,
Luckhardt
T
,
Hecker
L
, et al.
New insights into the pathogenesis and treatment of idiopathic pulmonary fibrosis
.
Drugs
.
2011
;
71
(
8
):
981
1001
.
9.
Sisson
TH
,
Mendez
M
,
Choi
K
, et al.
Targeted injury of type II alveolar epithelial cells induces pulmonary fibrosis
.
Am J Respir Crit Care Med
.
2009
;
181
(
3
):
254
263
.
10.
Selman
M
,
Pardo
A
.
Role of epithelial cells in idiopathic pulmonary fibrosis: from innocent targets to serial killers
.
Proc Am Thorac Soc
.
2006
;
3
(
4
):
364
372
.
11.
Thannickal
VJ
,
Horowitz
JC
.
Evolving concepts of apoptosis in idiopathic pulmonary fibrosis
.
Proc Am Thorac Soc
.
2006
;
3
(
4
):
350
356
.
12.
Cronkhite
JT
,
Xing
C
,
Raghu
G
, et al.
Telomere shortening in familial and sporadic pulmonary fibrosis
.
Am J Respir Crit Care Med
.
2008
;
178
(
7
):
729
737
.
13.
Heppleston
A
.
The pathology of honeycomb lung
.
Thorax
.
1956
;
1177
1193
.
14.
Pimentel
J
.
Tridimensional photographic reconstruction in a study of the pathogenesis of honeycomb lung
.
Thorax
.
1967
;
22
(
5
):
444
452
.
15.
Raghu
G
,
Weycker
D
,
Edelsberg
J
,
Bradford
WZ
,
Oster
G
.
Incidence and prevalence of idiopathic pulmonary fibrosis
.
Am J Respir Crit Care Med
.
2006
;
174
(
7
):
810
816
.
16.
Fernández Perez
ER
,
Daniels
CE
,
Schroeder
DR
, et al.
Incidence, prevalence, and clinical course of idiopathic pulmonary fibrosis: a population-based study
.
Chest
.
2009
;
137
(
1
):
129
137
.
17.
Steele
MP
,
Brown
KK
.
Genetic predisposition to respiratory diseases: infiltrative lung diseases
.
Respiration
.
2007
;
74
(
6
):
601
608
.
18.
Stemmermann
GN
.
Chronic familial lung disease
.
Am Rev Respir Dis
.
1967
;
95
(
4
):
663
669
.
19.
Swaye
P
,
Van Ordstrand
HS
,
McCormack
LJ
,
Wolpaw
SE
.
Familial Hamman-Rich syndrome: report of eight cases
.
Dis Chest
.
1969
;
55
(
1
):
7
12
.
20.
Solliday
N
,
Williams
J
,
Gaensler
E
,
Coutu
RE
,
Carrington
CB
.
Familial chronic interstitial pneumonia
.
Am Rev Respir Dis
.
1973
;
108
(
2
);
193
204
.
21.
Murphy
A
,
O'Sullivan
BJ
.
Familial fibrosing alveolitis
.
Ir J Med Sci
.
1981
;
150
(
7
):
204
209
.
22.
Marshall
RP
,
Puddicombe
A
,
Cookson
WO
,
Laurent
GJ
.
Adult familial cryptogenic fibrosing alveolitis in the United Kingdom
.
Thorax
.
2000
;
55
(
2
):
143
146
.
23.
Amin
RS
,
Wert
SE
,
Baughman
RP
, et al.
Surfactant protein deficiency in familial interstitial lung disease
.
J Pediatr
.
2001
;
139
(
1
):
85
92
.
24.
Lettieri
CJ
,
Nathan
SD
,
Browning
RF
,
Barnett
SD
,
Ahmad
S
,
Shorr
AF
.
The distance-saturation product predicts mortality in idiopathic pulmonary fibrosis
.
Respir Med
.
2006
;
100
(
10
):
1734
1741
.
25.
Kondoh
Y
,
Taniguchi
H
,
Kawabata
Y
,
Yokoi
T
,
Suzuki
K
,
Takagi
K
.
Acute exacerbation in idiopathic pulmonary fibrosis: analysis of clinical and pathologic findings in three cases
.
Chest
.
1993
;
103
(
6
):
1808
1812
.
26.
Collard
HR
,
Moore
BB
,
Flaherty
KR
, et al.
Acute exacerbations of idiopathic pulmonary fibrosis
.
Am J Respir Crit Care Med
.
2007
;
176
(
7
):
636
643
.
27.
Collard
HR
,
Calfee
CS
,
Wolters
PJ
, et al.
Plasma biomarker profiles in acute exacerbation of idiopathic pulmonary fibrosis
.
Am J Physiol Lung Cell Mol Physiol
.
2010
;
299
(
1
):
L3
L7
.
28.
Kondoh
Y
,
Taniguchi
H
,
Katsuta
T
, et al.
Risk factors of acute exacerbation of idiopathic pulmonary fibrosis
.
Sarcoidosis Vasc Diffuse Lung Dis
.
2010
;
27
(
2
):
103
110
.
29.
Simon-Blancal
V
,
Freynet
O
,
Nunes
H
, et al.
Acute exacerbation of idiopathic pulmonary fibrosis: outcome and prognostic factors [published online ahead of print August 12, 2011]
.
Respiration
.
doi:10.1159/000329891.
30.
Wootton
SC
,
Kim
DS
,
Kondoh
Y
, et al.
Viral infection in acute exacerbation of idiopathic pulmonary fibrosis
.
Am J Respir Crit Care Med
.
2011
;
183
(
12
):
1698
1702
.
31.
Tcherakian
C
,
Cottin
V
,
Brillet
PY
, et al.
Progression of idiopathic pulmonary fibrosis: lessons from asymmetrical disease
.
Thorax
.
66
(
3
):
226
231
.
32.
Hunninghake
GW
,
Lynch
DA
,
Galvin
JR
, et al.
Radiologic findings are strongly associated with a pathologic diagnosis of usual interstitial pneumonia
.
Chest
.
2003
;
124
(
4
):
1215
1223
.
33.
Liebow
A
,
Carrington
C
.
The interstitial pneumonias
.
In
:
Simon
M
,
Potchen
E
,
LeMay
M
,
eds
.
Frontiers of Pulmonary Radiology Pathophysiologic, Roentgenographic and Radioisotopic Considerations
.
Orlando, FL
:
Grune & Stratton
;
1969
:
109
142
.
34.
Raghu
G
,
Mageto
YN
,
Lockhart
D
,
Schmidt
RA
,
Wood
DE
,
Godwin
JD
.
The accuracy of the clinical diagnosis of new-onset idiopathic pulmonary fibrosis and other interstitial lung disease: a prospective study
.
Chest
.
1999
;
116
(
5
):
1168
1174
.
35.
Travis
W
,
King
T
,
Bateman
E
, et al
;
for American Thoracic Society/European International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias
.
ATS/ERS joint statement adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001 [erratum in Am J Respir Crit Care Med. 2002;166(3:426)]
.
Am J Respir Crit Care Med
.
2002
;
165
(
2
):
277
304
.
36.
Katzenstein
AL
,
Zisman
DA
,
Litzky
LA
,
Nguyen
BT
,
Kotloff
RM
.
Usual interstitial pneumonia: histologic study of biopsy and explant specimens
.
Am J Surg Pathol
.
2002
;
26
(
12
):
1567
1577
.
37.
Song
JW
,
Do
KH
,
Kim
MY
,
Jang
SJ
,
Colby
TV
,
Kim
DS
.
Pathologic and radiologic differences between idiopathic and collagen vascular disease-related usual interstitial pneumonia
.
Chest
.
2009
;
136
(
1
):
23
30
.
38.
Churg
A
,
Sin
DD
,
Everett
D
,
Brown
K
,
Cool
C
.
Pathologic patterns and survival in chronic hypersensitivity pneumonitis
.
Am J Surg Pathol
.
2009
;
33
(
12
):
1765
1770
.
39.
Cool
CD
,
Groshong
SD
,
Rai
PR
,
Henson
PM
,
Stewart
JS
,
Brown
KK
.
Fibroblast foci are not discrete sites of lung injury or repair: the fibroblast reticulum
.
Am J Respir Crit Care Med
.
2006
;
174
(
6
):
654
658
.
40.
Suki
B
,
Bates
JH
.
Lung tissue mechanics as an emergent phenomenon
.
J Appl Physiol
.
2011
;
110
(
4
):
1111
1118
.
41.
Tschumperlin
DJ
,
Boudreault
F
,
Liu
F
.
Recent advances and new opportunities in lung mechanobiology
.
J Biomech
.
2009
;
43
(
1
):
99
107
.
42.
Myers
JL
,
Katzenstein
AL
.
Epithelial necrosis and alveolar collapse in the pathogenesis of usual interstitial pneumonia
.
Chest
.
1988
;
94
(
6
):
1309
1311
.
43.
Galvin
JR
,
Frazier
AA
,
Franks
TJ
.
Collaborative radiologic and histopathologic assessment of fibrotic lung disease
.
Radiology
.
2010
;
255
(
3
):
692
706
.
44.
Colombat
M
,
Mal
H
,
Groussard
O
, et al.
Pulmonary vascular lesions in end-stage idiopathic pulmonary fibrosis: histopathologic study on lung explant specimens and correlations with pulmonary hemodynamics
.
Hum Pathol
.
2007
;
38
(
1
):
60
65
.
45.
Pitsiou
G
,
Papakosta
D
,
Bouros
D
.
Pulmonary hypertension in idiopathic pulmonary fibrosis: a review
.
Respiration
.
2011
;
82
(
3
):
294
304
.
46.
Honda
Y
,
Tsunematsu
K
,
Suzuki
A
,
Akino
T
.
Changes in phospholipids in bronchoalveolar lavage fluid of patients with interstitial lung diseases
.
Lung
.
1988
;
166
(
5
):
293
301
.
47.
Robinson
PC
,
Watters
LC
,
King
TE
,
Mason
RJ
.
Idiopathic pulmonary fibrosis. Abnormalities in bronchoalveolar lavage fluid phospholipids
.
Am Rev Respir Dis
.
1988
;
137
(
3
):
585
591
.
48.
McCormack
FX
,
King
TE
Jr.,
Voelker
DR
,
Robinson
PC
,
Mason
RJ
.
Idiopathic pulmonary fibrosis: abnormalities in the bronchoalveolar lavage content of surfactant protein A
.
Am Rev Respir Dis
.
1991
;
144
(
1
):
160
166
.
49.
Kuroki
Y
,
Tsutahara
S
,
Shijubo
N
, et al.
Elevated levels of lung surfactant protein A in sera from patients with idiopathic pulmonary fibrosis and pulmonary alveolar proteinosis
.
Am Rev Respir Dis
.
1993
;
147
(
3
):
723
729
.
50.
Lenz
AG
,
Meyer
B
,
Costabel
U
,
Maier
K
.
Bronchoalveolar lavage fluid proteins in human lung disease: analysis by two-dimensional electrophoresis
.
Electrophoresis
.
1993
;
14
(
3
):
242
244
.
51.
Honda
Y
,
Kuroki
Y
,
Matsuura
E
, et al.
Pulmonary surfactant protein D in sera and bronchoalveolar lavage fluids
.
Am J Respir Crit Care Med
.
1995
;
152
(
6, pt 1
):
1860
1866
.
52.
Honda
Y
,
Kuroki
Y
,
Shijubo
N
, et al.
Aberrant appearance of lung surfactant protein A in sera of patients with idiopathic pulmonary fibrosis and its clinical significance
.
Respiration
.
1995
;
62
(
2
):
64
69
.
53.
McCormack
FX
,
King
TE
, Jr.,
Bucher
BL
,
Nielsen
L
,
Mason
RJ
,
McCormac
FX
.
Surfactant protein A predicts survival in idiopathic pulmonary fibrosis
.
Am J Respir Crit Care Med
.
1995
;
152
(
2
):
751
759
.
54.
McFadden
RG
.
Surfactant protein A predicts survival in idiopathic pulmonary fibrosis [comment on Am J Respir Crit Care Med. 1995;152(2):751–759]
.
Am J Respir Crit Care Med
.
1996
;
154
(
3, pt 1
):
825
856
.
55.
Gunther
A
,
Schmidt
R
,
Nix
F
, et al.
Surfactant abnormalities in idiopathic pulmonary fibrosis, hypersensitivity pneumonitis and sarcoidosis
.
Eur Respir J
.
1999
;
14
(
3
):
565
573
.
56.
Takahashi
H
,
Fujishima
T
,
Koba
H
, et al.
Serum surfactant proteins A and D as prognostic factors in idiopathic pulmonary fibrosis and their relationship to disease extent
.
Am J Respir Crit Care Med
.
2000
;
162
(
3, pt 1
):
1109
1114
.
57.
Rugonyi
S
,
Biswas
SC
,
Hall
SB
.
The biophysical function of pulmonary surfactant
.
Respir Physiol Neurobiol
.
2008
;
163
(
13
):
244
255
.
58.
Avery
M
,
Mead
J
.
Surface properties in relation to atelectasis and hyaline membrane disease
.
Am J Dis Child
1959
;
97
:
517
523
.
59.
Whitsett
JA
,
Wert
SE
,
Weaver
TE
.
Alveolar surfactant homeostasis and the pathogenesis of pulmonary disease
.
Annu Rev Med
.
2010
;
61
;
105
119
.
60.
Wert
SE
,
Whitsett
JA
,
Nogee
LM
.
Genetic disorders of surfactant dysfunction
.
Pediatr Dev Pathol
.
2009
;
12
(
4
):
253
274
.
61.
Cosgrove
GP
,
Brown
KK
,
Schiemann
WP
, et al.
Pigment epithelium-derived factor in idiopathic pulmonary fibrosis: a role in aberrant angiogenesis
.
Am J Respir Crit Care Med
.
2004
;
170
(
3
):
242
251
.
62.
Tobin
RW
,
Pope
CE II
,
Pellegrini
CA
,
Emond
MJ
,
Sillery
J
,
Raghu
G
.
Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis
.
Am J Respir Crit Care Med
.
1998
;
158
(
6
):
1804
1808
.
63.
Lee
JS
,
Ryu
JH
,
Elicker
BM
, et al.
Gastroesophageal reflux therapy is associated with longer survival in idiopathic pulmonary fibrosis [published online ahead of print June 23, 2011]
.
Am J Respir Crit Care Med
.
doi:10.1164/rccm.201101-0138OC.
64.
Sakamoto
K
,
Taniguchi
H
,
Kondoh
Y
,
Ono
K
,
Hasegawa
Y
,
Kitaichi
M
.
Acute exacerbation of idiopathic pulmonary fibrosis as the initial presentation of the disease
.
Eur Respir Rev
.
2009
;
18
(
112
):
129
132
.

Author notes

From the Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale.

The authors have no relevant financial interest in the products or companies described in this article.