Etiology & Pathogenesis

 

Etiology

The etiology of most chronic human diseases are complex, involving a mix of genetic and environmental influences, interacting with each other over time resulting in health or disease.

 

Science ILD development graphic

Evidence for a genetic role in Pulmonary fibrosis (PF):

  • clusters in families1,2
  • Occurs in pleiotropic genetic disorders***3
  • Inbred strains of mice demonstrate variable susceptibility to fibrogenic agents.4,5,6,7

Some individuals, perhaps by virtue of defective repair mechanisms, may simply be less capable of dealing with the burden of fibrogenic challenges that are experienced throughout life.

Genetic predisposition for pulmonary fibrosis is an important factor for the development of disease.  Knowledge regarding the genes involved in familial pulmonary fibrosis (FPF) is emerging.  Identification of these genes is a major focus of the FPF study.   

For more information on the genetic causes of FPF, please see the Genetics section.

 

Environmental Exposures:

 A number of exposures have been found to be associated with the development of IPF/UIP.

 

Cigarette Smoke

IPF is found more frequent in cigarette smokers.8,9   Even in FIP, cigarette smoking was the strongest associated risk factor.1  Though it is known that cigarette smoke increases the risk for PF, it is not been identified as a cause of pulmonary fibrosis.

 

Metal & Wood Dust

***Epidemiological studies have established a consistent association between metal and wood dust exposure and IPF in several parts of the world, such as the USA10, Britain11,12 & Japan.13,14  

The duration of average daily exposure and the overall length of exposure to metal or wood dust were significantly related to the development of IPF, supporting a dose-response relationship.11

 

Viral Infections

Although controversial, an association of herpesvirus with IPF has been developed most clearly for Epstein Barr Virus, but there is evidence that Cytomegalovirus and other viruses may be relevant.
Several viruses have been associated with pulmonary fibrosis:15,16,17

  • Epstein Barr Virus

  • Cytomegelovirus

  • Hepatitis C

  • HHV-8

One or more of these viruses have been detected via PCR or immunohistochemistry in the lungs of up to 97% of tested IPF patients.15,31  The hypothesis that viral infection can lead to pulmonary fibrosis is not uncontested. In fact, it has been suggested that the immunosuppressive treatment used to treat IPF results in reactivation of innocuous latent viral infections.27

 

Drugs

***Drugs that have been linked to or found causative for ILDs include some antiobiotics, anti-arrhythimics, neurotropics, psychotropics, chemotherapeutic agents and others.32,33,34 

A more comprehensive list of drugs can be found in Interstitial Lung Disease, ed.4 by Marvin I. Schwartz, MD and Talmadge A. King, Jr., MD (ISBN:1-55009-179-4)

 

Occupational Exposures

A growing list of workplace exposures are being identified as causes or risk factors for ILDs. Some of these exposures include asbestos, silica, avian antigens, and other inhaled particles. Even within occupational exposures and subsequent interstitial lung disease, considerable variability exists. This suggests genetic susceptibility is also playing a role in the development of disease.24

 

 

Pathogenesis

The pathogenesis of idiopathic interstitial pneumonias (IIP).  However, abnormal processes in injury and repair mechanisms in the lung is generally agreed upon in the development of interstitial lung disease (ILD).  An injury to the alveolar epithelial cells initiates a pathological sequence resulting in an inflammatory response resulting in fibrosis responsible for physiological abnormalities.23

Initial injury can be introduced by the inhalation of mineral fibers or dusts, as is common in occupational lung diseases, or from the result of sensitization to inhaled antigens from environment. The circulation system can be another route for injury as in the case of drug-induced interstitial lung disease.23

 

Development of Pulmonary Fibrosis

The lungs are constantly exposed to the environment and are at constant risk of microscopic and macroscopic environmental injury (see diagram above).

Approximately 11,000 liters of air come in contact with the respiratory system daily, containing such noxious agents as dusts, fumes, microbes, aerosolized toxins, and pollutants. One can therefore argue that lung injury is the rule rather than the exception and that pulmonary wound healing and tissue repair are ongoing processes in the life of an individual.

A fine equilibrium must be maintained to facilitate healing without excessive scarring. Excessive injury or genetic predisposition (or both) leads to an imbalance between the wound healing and progressive scarring with either the development of ILD or return to normal lung parenchyma.

It is possible that pulmonary fibrosis develops as a result of extensive lung injury, aberrant repair mechanisms, or a combination of both.

Although we know that extensive lung injury can result in pulmonary fibrosis (e.g., asbestosis), considerable variability in the extent of fibrosis exists between those individuals exposed to similar concentrations of this fibrogenic agent.24

 

 

References

  1. Steele et al., Clinical and pathologic features of familial interstitial pneumonia. Am Respir Crit Care Med 172:1146-1152 (2005).

  2. Marshall et al., Adult familial cryptogenic fibrosing alveolitis in the United Kingdom. Thorax 55:143-146 (2000).

  3. ***

  4. Rossi et al., Susceptibility to experimental interstitial lung disease is modified by immune- and non-immune related genes. Am Rev Respir Dis. 135:448-55 (1987).

  5. Ortiz et al. Expression of TNF and the necessity of TNF receptors in bleomycin- induced lung injury in mice. Exp Lung Res. 24(6):721-43 (1998).

  6. Corsini et al., A protective role for T lymphocytes in asbestos-induced pulmonary inflammation and collagen deposition. Am J Respir Cell Mol Biol. 11:531-9 (1994).

  7. Warshamana et al., Susceptibility to asbestos-induced and transforming growth factor-beta1-induced fibroproliferative lung disease in two strains of mice. Am J Respir Cell Mol Biol. 27(6):705-13 (2002).

  8.  Baumgartner et al., Cigarette smoking: A risk factor for idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 155:242-8 (1997).

  9. Schwartz et al. Determinants of progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 149:444-9 (1994).

  10. Baumgartner et al. Occupational and environmental risk factors for idiopathic pulmonary fibrosis: a multicenter case-control study. Collaborating Centers. Am J Epidemiol. 152(4):307-15 (2000).

  11. Hubbard et al., Occupational exposure to metal or wood dust and aetiology of cryptogenic fibrosing alveolitis. Lancet. 347:284-9 (1996).

  12. Hubbard et al. Risk of cryptogenic fibrosing alveolitis in metal workers. Lancet. 5;355(9202):466-7 (2000)

  13. Iwai K, Mori T, Yamada N, Yamaguchi M, Hosoda Y. Idiopathic pulmonary fibrosis. Epidemiologic approaches to occupational exposure. Am J Respir Crit Care Med. 150:670-5 (1994).

  14. Miyake Y, Sasaki S, Yokoyama T, Chida K, Azuma A, Suda T, et al. Occupational and environmental factors and idiopathic pulmonary fibrosis in Japan. Ann Occup Hyg. 49(3):259-65 (2005).

  15. Tang et al., Herpesvirus DNA is consistently detected in lungs of patients with idiopathic pulmonary fibrosis. J Clin Microbiol. 41(6):2633-40 (2003).

  16. Yonemaru et al., Elevation of antibodies to cytomegalovirus and other herpes viruses in pulmonary fibrosis. Eur Respir J. 10(9):2040-2045 (1997).

  17. Lawson et al., Endoplasmic reticulum stress in alveolar epithelial cells is prominent in IPF: association with altered surfactant protein processing and herpesvirus infection.Am J Physiol Lung Cell Mol Physiol. 294(6):L1119-1126 (2008).

  18. Egan et al., Epstein-Barr virus replication within pulmonary epithelial cells in cryptogenic fibrosing alveolitis. Thorax. 50(12):1234-9 (1995).

  19. Kuwano et al. Detection of adenovirus E1A DNA in pulmonary fibrosis using nested polymerase chain reaction. Eur Respir J. 10:1445-9 (1997).

  20. Hubbard et al., Exposure to commonly prescribed drugs and the etiology of cryptogenic fibrosing alveolitis: a case-control study. Am J Respir Crit Care Med 157(3):743-747 (1998).

  21. Musk et al., Pindolol and pulmonary fibrosis. Br Med J.  2(6190):581-582 (1979).

  22. Erwteman et al., Interstitial pulmonary fibrosis: a new side effect of practolol. Br Med J. 2(6082):297-298 (1977).

  23. Schwartz, MI and King,TE. Interstitial Lung Disease, Fourth Edition Hamilton: BC Decker Inc., 2003.

  24. Selikoff et al., Asbestos disease in United States shipyards. Annals of the New York Academy of Sciences. 330:293-311 (1979).