1. IPF Overview With a Focus on Pathophysiology and Pathogenesis
SECTION 1
IPF Overview With a Focus on Pathophysiology and Pathogenesis

2. Objective
Discuss evolving concepts in the pathophysiology and pathogenesis of IPF

3. Evolving Classification of IPF
Interstitial Lung Diseases
UIP/IPF
Sarcoidosis
Hypersensitivity Pneumonitis
DIP
RB- ILD
A heterogeneous group that included a number of diseases
AIP
1970s
2002
NSIP
Cellular
Fibrotic
Evolving Classification of IPF
In preceding decades, a group of diseases known as idiopathic interstitial pneumonias (IIPs) tended to be lumped into broad classifications. Although these IIPs were recognized as distinct from other diffuse parenchymal lung diseases (DPLDs), such as sarcoidosis and hypersensitivity pneumonitis, no standard existed for classifying these separate IIPs. As a result, the diagnostic criteria and terminology used in reference to the IIPs was variable and confusing.
Several medical developments have prompted the creation of a new classification system for the IIPs. Specifically, the widespread use and understanding of high-resolution computed tomography has improved our knowledge of the extent and severity of the IIPs, and less invasive lung biopsy surgery has increased the availability of tissue study. Furthermore, publications relating pathologic descriptions with clinical course and responsiveness to treatment have allowed reclassification of the IIPs.
This new classification of IIPs has sparked a new interest in attempting to understand the pathogenesis of these diseases.
American Thoracic Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2002;165:
COP
Asbestosis
LAM
etc
LIP
Adapted from ATS/ERS Consensus Statement. Am J Resp Crit Care Med.
2002;165:

4. Current Definition of IPF
A distinct type of chronic fibrosing interstitial pneumonia of unknown cause, limited to the lungs, and associated with a surgical lung biopsy showing a histologic pattern of UIP
Current Definition of IPF
IPF is a distinct type of chronic fibrosing interstitial pneumonia of unknown cause, limited to the lungs, and associated with a surgical lung biopsy, showing a histologic pattern of UIP. The CT scan on the left shows a subpleural distribution of reticular opacities.The biopsy specimen on the right shows a transition from normal lung to fibrosis that illustrates the heterogeneous nature of IPF pathology.
American Thoracic Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2002;165:
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International Consensus Statement. Am J Respir Crit Care Med. 2000;161:
ATS/ERS Consensus Statement. Am J Resp Crit Care Med. 2002;165:
ATS/ERS Consensus Statement. Am J Resp Crit Care Med. 2000;161:

5. Potential Risk Factors
Familial (genetic)
Smoking
Environmental factors (eg, occupational exposure to wood dust or metal dust)
Chronic aspiration associated with gastroesophageal reflux disease (GERD)
Infectious agents
Potential Risk Factors
Although the etiology of IPF is not completely understood, certain factors have been associated with an increased risk of the disease. Heredity is generally considered a potential contributor because of familial cases of the disease, yet no specific genetic markers to explain this risk have been identified.
Some case-controlled studies have shown an odds ratio of approximately 2 among long-term smokers. On the other hand, patients actively smoking at the time of IPF diagnosis appear to have an increased survival.
Various environmental exposures in both rural and urban settings have been linked to the development of pulmonary fibrosis. Among these exposures, dust containing steel, brass, lead, and pinewood are most specifically linked to lung fibrosis. These environmental associations must be considered with caution, for many studies attempting to define such risk have relied solely on the clinical diagnosis of fibrosis without the use of HRCT or lung biopsy.
GERD has been implicated as a potential risk for developing this disease, although the role of chronic aspiration in the development of IPF is unclear. In the case of infectious agents, numerous viruses have been implicated as pathogenic factors in the development of IPF, yet again, no clear evidence for a viral etiology exists. The associated viruses include Epstein-Barr virus (EBV), influenza, cytomegalovirus (CMV), hepatitis C virus, parainfluenza 1 virus, human immunodeficiency virus 1 (HIV-1), measles virus, parainfluenza 3 virus, and herpes virus 6. Furthermore, exposure to antidepressant medication has been suggested as a risk factor for the development of IPF (not shown on slide).
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. Am J Respir Crit Care Med. 2000;161:
ATS/ERS Consensus Statement. Am J Resp Crit Care Med. 2000;161:

6. US Demographics Incidence: > 30,000 patients/year
Prevalence: > 80,000 current patients
Age of onset: 40 to 70 years
Two-thirds > 60 years old at presentation
Males > females
Caucasians > minorities
US Demographics
IPF is not a rare disease. Approximately 80,000 cases of IPF have been identified in the US, with an estimated 30,000 new cases developing each year. Without a good explanation, IPF is a disease of older people. Typically, patients present between the ages of 40 and 70 years, and approximately 66% of patients are over 60 years old at presentation. The mean age at diagnosis is 66 years, and the prevalence for people ages 35 to 44 years is 2.7 cases per 100,000 while the prevalence for people > 75 years of age exceeds 175 cases per 100,000. There is a slight male preponderance of disease, and the age-adjusted mortality rate for Caucasian patients exceeds that for African American patients.
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International Consensus Statement. Am J Respir Crit Care Med. 2000;161:
Weycker D, Oster G, Edelsberg J, et al. Economic costs of idiopathic pulmonary fibrosis. Paper presented at: CHEST 2002, November 2-7, 2002; San Diego, California.
ATS/ERS Consensus Statement. Am J Resp Crit Care Med. 2000;161:
Weycker D, et al. Prevalence, Incidence, and Economic Costs of Idiopathic Pulmonary Fibrosis.
Paper presented at: CHEST 2002, November 2-7, 2002; San Diego, California.

7. Epidemiology of IPF Incidence Prevalence
120
300
100
Male
250
Male 80
Female
200
Female 60
150 40
100 20 50
Epidemiology of IPF
This slide reiterates that the incidence and prevalence of IPF increases with age, and that the disease is more common in men than women. Because IPF is a chronic disease that is almost uniformly fatal, the ratio of the prevalence to the incidence can provide a crude indication of the duration of survival after diagnosis.
Weycker D, Oster G, Edelsberg J, et al. Economic costs of idiopathic pulmonary fibrosis. Paper presented at: CHEST 2002, November 2-7, 2002; San Diego, California.
45-54
55-64
65-74
75+
45-54
55-64
65-74
75+
Estimated 31,000 New Patients per Year in the United States
Estimated 83,000 Current Patients in the United States
Weycker D, et al. Prevalence, Incidence, and Economic Costs of Idiopathic Pulmonary Fibrosis.
Paper presented at: CHEST 2002, November 2-7, 2002; San Diego, California.

8. Survival Curve for IIP Patients Grouped by Histologic Classification
1.0
NSIP (n = 30)
0.9
0.8
0.7
0.6
Discordant UIP (n = 28)
0.5
Cumulative Proportion Surviving
0.4
0.3
Concordant UIP
(n = 51)
0.2
P <0.0003
Survival Curve for IIP Patients Grouped by Histologic Classification
Flaherty and colleagues demonstrated that variability in lobar histology is frequent among patients with idiopathic interstitial pneumonia, and patients with a pattern of UIP in any lobe should be classified as having UIP. They examined surgical lung biopsies from 109 patients, who had multiple lobes biopsied, and found that 51 patients had UIP in all biopsy specimens (concordant UIP), 28 patients had UIP in at least one but not all biopsy specimens (discordant UIP), 30 patients had NSIP in all biopsy specimens (NSIP).
This slide shows the Kaplan-Meier survival curves for patients with concordant UIP, discordant UIP, and NSIP, and demonstrates that patients with NSIP have a significantly prolonged survival (P < ). When evaluated independently, survival among both UIP groups demonstrated no significant difference (P = 0.16), while patients with NSIP had a significant survival advantage over both discordant UIP patients (P < ) and concordant UIP patients (P < ). The risk of mortality for patients with concordant UIP and discordant UIP was 24.3 and 16.8 times greater than patients with NSIP, respectively.
The study raises questions about the natural history and pathogenesis of NSIP and UIP. Specifically, are NSIP and UIP part of a continuum of disease where NSIP is an early form of UIP?
Flaherty KR, Travis WE, Colby TV, et al. Histopathologic variability in usual and non-specific interstitial pneumonias. Am J Respir Crit Care Med. 2001;164:
0.1
0.0
Time (years)
Flaherty KR, et al. Am J Respir Crit Care Med. 2001;164:

9. UIP: A Histologic Study of Biopsy and Explant Specimens
Areas resembling NSIP often present in UIP
If areas of NSIP and UIP are both present, UIP determines prognosis
Potential confounding histologic features may be present in UIP
Acute process superimposed on UIP
Diffuse alveolar damage and BOOP superimposed on UIP
Extensive honeycomb change may obscure diagnosis of UIP
UIP: A Histologic Study of Biopsy and Explant Specimens
Katzenstein and colleagues found in a review of biopsy and subsequent explant specimens of 20 patients with UIP that areas resembling NSIP are present in the majority of UIP specimens and are often extensive. They noted that in cases with areas of both UIP and NSIP on pathologic specimen, the prognosis was determined by the UIP. They demonstrated that other findings, including acute processes, diffuse alveolar damage, BOOP, and/or extensive honeycomb change, in addition to prominent NSIP can confound the diagnosis of UIP.
These investigators argue against the evolution of NSIP into UIP with evidence that no patients with UIP specimens at explant had a previous biopsy showing NSIP, instead suggesting that the coexistence of NSIP and UIP represents two distinct processes.
Katzenstein ALA, Zisman DA, Litzky LA, Nguyen BT, Kotloff RM. Usual interstitial pneumonia. Histologic study of biopsy and explant specimens. Am J Surg Pathol. 2002;26:
Katzenstein AA, et al. Am J Surg Pathol. 2002;26(12):

10. UIP Gene Chip Data Groups of genes significantly overexpressed in UIP
Muscle markers
Extracellular matrix, growth factors, and proteases
Cytokines, chemokines, and antioxidants
Complement, immunoglobulins, and amyloid
UIP Gene Chip Data
Recent research has identified groups of genes that are significantly overexpressed in the lung tissue of patients with UIP, although the molecular mechanisms leading to pulmonary fibrosis are poorly understood. These data taken together support an emerging hypothesis that disordered and persistent remodeling of the pulmonary interstitium by fibroblasts and smooth muscle cells results in the pathologic process of fibrosis.
Specifically, Zuo and colleagues demonstrated, in documented cases of UIP, the overexpression of genes encoding muscle proteins that stimulated growth and differentiation and could result in the development of fibroblastic foci. These markers of muscle proteins included vascular a smooth muscle actin, γ smooth muscle actin, calponin, and integrin a7b1. Interestingly, these investigators did not identify an increase in expression of genes encoding proinflammatory cytokines, such as IL-1 and TNF-alpha. However, genes encoding certain immunoglobulins and chemokines were overexpressed. As would be expected, the genes that encode for extracellular matrix proteins, such as collagens, demonstrated increased expression in fibrotic lung tissue as were the genes encoding specific matrix metalloproteinases. In particular, the expression level of the matrix metalloproteinase, MMP-7 (matrilysin), was the most informative increase. When the gene encoding for MMP-7 was knocked out of mice that were subsequently given intratracheal bleomycin, pulmonary fibrosis did not develop.
Zuo F, Kaminski N, Eugui E, et al. Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. Proc Nat Acad Sci USA. 2002;99:
Zuo F, et al. Proc Natl Acad Sci USA. 2002;99(9):

11. Age Genetic factors Environmental factors Nature of injury
Histopathological Patterns of IIPs
LUNG INJURY
Age Genetic factors Environmental factors Nature of injury
– Etiologic agent
– Recurrent vs single
– Endothelial vs epithelial
Histopathologic Pattern
Histopathological Patterns of IIPs
A recent review of the mechanisms of pulmonary fibrosis by Thannickal and colleagues explained how histopathologic changes in the lung can be quite diverse with overlapping patterns of inflammation and fibrosis.
“Histopathologic patterns of idiopathic interstitial pneumonias (IIPs) represent a spectrum of tissue reactions with varying degrees of inflammation and fibrosis. This reaction pattern probably depends on multiple factors, including age, genetic susceptibility, environmental factors, and perhaps the nature of the injurious agent.”
Thannickal VJ, Toews GB, White ES, Lynch III JP, Martinez FJ. Mechanisms of pulmonary fibrosis. Annu Rev Med. 2004;55:
DIP
RB-ILD
LIP
COP
NSIP
AIP
UIP
Inflammation
Fibrosis
Thannickal VJ, et al. Annu Rev Med. 2004;55:

12. What Is the Natural History of UIP/IPF?
Natural History/Pathogenesis of Disease
What Is the Natural History of UIP/IPF?
In order to better understand the pathogenesis of UIP/IPF, it is critical to evaluate the natural history of the disease from a pathologic standpoint. Unfortunately, in the absence of longitudinal studies in which untreated patients undergo serial biopsies, it will be difficult to fully evaluate the pathologic progression of the disease. Therefore, it is unclear at this point whether the pathology of IPF begins as UIP and remains unchanged as the disease progresses, or (as depicted in the next slide) begins as a predominantly cellular pattern that progresses to UIP over time.
Beginning
Intermediate
End Stage
Stage/Phase
Slide courtesy of Robert Strieter, MD

13. A Potential Natural History of the Pathogenesis of NSIP  UIP
NSIP-F
End Stage
UIP
A Potential Natural History of the Pathogenesis of NSIP  UIP
While controversial, recent evidence suggests that the process begins with a predominately cellular pattern of disease as seen in NSIP (cellular) and progresses to an end-stage picture of fibrosis as seen in UIP. The intermediate stage is represented by NSIP-F (fibrotic) which has both cellular and fibrotic components.
Flaherty KR, Travis WE, Colby TV, et al. Histopathologic variability in usual and non-specific interstitial pneumonias. Am J Respir Crit Care Med. 2001;164:
Beginning
Intermediate
Stage/Phase
Flaherty KR, et al. Am J Respir Crit Care Med. 2001;164: Slide courtesy of Robert Strieter, MD

14. Progression of IPF: Acute Exacerbation vs Slow Decline
Traditional View of UIP/IPF Progression
Function/Symptoms
Respiratory
FVC
50%
Progression of IPF: Acute Exacerbation vs Slow Decline
The traditional view of IPF progression involved a slow and steady decline in respiratory function as illustrated by this chart. According to this view, the progressive decline in lung function ultimately leads to respiratory failure and death. 1 2 3 4
Years
FVC = forced vital capacity

15. Progression of IPF: Acute Exacerbation vs Slow Decline
Step Theory of UIP/IPF Progression
Function/Symptoms
Respiratory
FVC
50%
Acute exacerbation
Progression of IPF: Acute Exacerbation vs Slow Decline
Emerging evidence suggests that IPF may involve multiple injuries or “hits” to the lung over a period of time, and these hits lead to acute exacerbations that result in periods of more rapid decline in lung function. In other words, this step theory of IPF progression posits that IPF involves many subclinical events with superimposed acute exacerbations that lead to functional decline. These acute exacerbations can be mild or severe and lead to a precipitous decline in respiratory function, respiratory failure, and death. 1 2 3 4
Years

16. Progression of Lung Fibrosis
Injury
Epithelial cells
Progression of Lung Fibrosis
While the etiology of IPF remains unknown, several recent observations have led to the theory that IPF is the result of an aberrant wound healing process.
According to this theory, injury to the alveolar epithelial and capillary wall lining stimulates the release of molecules that damage the basement membrane. In the absence of an appropriate substrate, re-epithelialization and re-endothelialization cannot occur and, in an attempt to “wall off” the exposed area, chemokines and growth factors recruit fibroblasts and endothelial cells, which are stimulated to produce collagen and other matrix components.
Capillary
Slide courtesy of Paul Noble, MD

17. Tissue Model of Lung Fibrosis
Cell death
Epithelial cells
Growth factors and other
products of epithelial
cell Injury
Capillary
Myofibroblast
Tissue Model of Lung Fibrosis
As discussed on the previous slide, according to this theory, injury to the alveolar and capillary walls stimulates the release of molecules that damage the basement membrane. In the absence of an appropriate substrate, re-endothelialization cannot occur and, in an attempt to “wall off” the exposed area, chemokines and growth factors recruit fibroblasts and endothelial cells, which are stimulated to produce collagen and other matrix components.
Specifically, injury to the alveolar and capillary walls leads to tissue damage and cell death. This cell death is accompanied by damage to the basement membrane and the release of a variety of factors, including growth factors and cytokines. Many of these factors stimulate fibroblasts to produce extracellular matrix components (particularly collagen), and can lead to dysregulated repair of the epithelial/endothelial barrier. In the end, the formation of fibrotic regions of extracellular matrix proteins and myofibroblasts impedes the recovery of the normal alveolar wall.
Collagen
Slide courtesy of Paul Noble, MD

18. Peripheral Accentuation of Disease
Pathology of IPF:
Peripheral Accentuation of Disease
Pathology of IPF: Peripheral Accentuation of Disease
This is a low-powered view of lung tissue from a patient with IPF. It is evident that the disease is accentuated in the periphery. In other words, there is fibrosis at the periphery of the lung, surrounding and transitioning to normal lung architecture centrally.
Slide courtesy of Kevin Leslie, MD

19. Pathology of IPF: Transition to Uninvolved Lung Present in the Biopsy
In this intermediate power view of IPF lung tissue, the heterogeneous nature of the disease is clear. There is a transition from areas of normal lung tissue to areas of fibrosis, fibroblastic foci, and cellular infiltrate.
Slide courtesy of Kevin Leslie, MD

20. Pathology of UIP/IPF Slide courtesy of Kevin Leslie, MD
This pathologic sample is a high-powered view of UIP, again showing normal alveolar structure to the left and fibrosis to the right. Note the presence of the concentrated area of fibroblast proliferation, known as a fibroblastic focus.
Slide courtesy of Kevin Leslie, MD

21. Fibroblastic Focus in UIP
Fibroblastic Foci in UIP
This is an example of a fibroblastic focus, a characteristic feature of UIP. They are typically not seen in other idiopathic interstitial pneumonias. Fibroblastic foci are usually at the leading edge of an area of fibrosis (region where fibrosis transitions to normal lung).
Slide courtesy of Kevin Leslie, MD

22. IPF: Potential Contributing Pathways CHEMOTAXIS/ACTIVATION
GROWTH
FACTOR
ANGIOSTATIC
CHEMOKINES
DIRECT
MARKERS
OF FIBROSIS
IMMUNOMODULATING
CYTOKINES AND
CHEMOKINES
ANGIOGENIC FACTORS
NEUTROPHIL
CHEMOTAXIS/ACTIVATION
IPF: Potential Contributing Pathways
In the end, we are unclear about the precise elements that are involved in the pathogenesis of IPF, but we have learned a great deal and gained valuable insights into this complicated process from recent studies. By exploring the direct markers of fibrosis in the lung tissue of patients with IPF, certain factors have been implicated as potential contributors to this disease, and these factors are areas of active research into pathways that may be targets for therapeutic intervention. Such pathways include growth factors, angiogenic factors, chemokines, cytokines, and antimicrobial factors.
ANTIMICROBIAL
FACTORS
Slide courtesy of Robert Strieter, MD