Pulmonary Fibrosis, Idiopathic
A number sign (#) is used with this entry because some cases of idiopathic pulmonary fibrosis (IPF) are caused by heterozygous mutation in the SFTPA2 gene (178642), encoding pulmonary surfactant protein A2, on chromosome 10q22.
Evidence suggests that susceptibility to the disease may also be conferred by a polymorphism in the SFTPA1 gene (178630) on chromosome 10q22 or a promoter mutation in the MUC5B gene (600770) on chromosome 11p15.
DescriptionIdiopathic pulmonary fibrosis is one of a family of idiopathic pneumonias sharing clinical features of shortness of breath, radiographically evident diffuse pulmonary infiltrates, and varying degrees in inflammation, fibrosis, or both on lung biopsy. In some cases, the disorder can be rapidly progressive and characterized by sequential acute lung injury with subsequent scarring and end-stage lung disease. Although older studies included several forms of interstitial pneumonia under the term 'idiopathic pulmonary fibrosis,' the clinical label of 'idiopathic pulmonary fibrosis' should be reserved for patients with a specific form of fibrosing interstitial pneumonia referred to as usual interstitial pneumonia (Gross and Hunninghake, 2001). It is estimated that 0.5 to 2.2% of cases of idiopathic pulmonary fibrosis are familial (Marshall et al., 2000).
Pulmonary fibrosis can also be a feature in patients with mutations in the TERT (187270) or the TERC (602322) gene; see PFBMFT1 (614742) and PFBMFT2 (614743).
Some patients with surfactant protein C deficiency (610913) who survive to adulthood manifest features of pulmonary fibrosis.
Clinical FeaturesMcKusick and Fisher (1958) described 3 cases. Donohue et al. (1959) reported a Canadian family with 8 cases in 4 generations, and Rezek and Talbert (1962) reported father and daughter.
Jacox et al. (1964) described a family in which idiopathic pulmonary fibrosis had been observed in 8 definite and 3 probable instances in a dominant pedigree pattern. Apparent male-to-male transmission had occurred in 1 instance. Increase of a gamma-globulin fraction was thought to be a possible integral part of the syndrome. Hughes (1964) described the disorder in a mother and 2 daughters. Davies and Potts (1964) observed affected brothers in whom clubbing of the fingers was present for many years before the development of respiratory symptoms.
Koch (1965) observed a family with 3 definite and 5 probable cases. The definite cases included an instance of father-to-son transmission; one patient developed bronchial carcinoma. Swaye et al. (1969) described 8 cases in 3 generations. In 1 case, the diagnosis was made at age 3.5 years by lung biopsy. Two brothers had coexistent pulmonary fibrosis and bronchogenic cancer.
Wagley (1972) described a family in which 3 brothers and a sister had well-documented pulmonary fibrosis and their mother, 2 of their sibs, and the son of 1 brother probably had pulmonary fibrosis.
Gadek et al. (1979) found high concentrations of collagenase in the lower respiratory tract of patients with idiopathic pulmonary fibrosis.
Beaumont et al. (1981) reported the occurrence of interstitial pulmonary fibrosis and alveolar cell carcinoma (ACC) in a family. At the time of report, 5 members had pulmonary fibrosis, of whom 3 had ACC. A sixth member had ACC without proven pulmonary fibrosis. Ten Kate (1981) stated that 1 of the 2 with pulmonary fibrosis without ACC had developed ACC. ACC with familial pulmonary fibrosis was reported by McKusick and Fisher (1958).
In familial idiopathic pulmonary fibrosis, there is a characteristic pattern of alveolar inflammation that features neutrophil accumulation and macrophage activation. Bitterman et al. (1986) found that, despite being clinically normal in every respect, about half the first-degree relatives of patients with familial idiopathic fibrosis (they studied 3 families) had a similar pattern of alveolar inflammation. From studies of 5 patients with idiopathic pulmonary fibrosis, Antoniades et al. (1990) suggested that overproduction of platelet-derived growth factor-beta (190040) may play an important role in pathogenesis.
Farrell et al. (1986) described a family in which 3 members had a parenchymal pulmonary disorder beginning in infancy. At age 4 months, the proposita had several upper respiratory infections and thereafter insidiously developed progressive respiratory failure. The authors reported proliferation and desquamation of type II pneumonocytes filling the alveolar spaces. Electron microscopy showed that the pneumocytes contained abundant lamellar bodies in the cytoplasm. The paternal uncle and aunt of the proposita died at 8 and 7 months, respectively. In the last month of life, each had lung biopsy which showed proliferation of alveolar cells, diffuse pulmonary fibrosis, and cystic changes suggestive of idiopathic pulmonary fibrosis. Steroids were not effective in the proposita, but chloroquine was dramatically beneficial. After 4 months of treatment, repeat lung biopsy showed great improvement and at the time of report the child, aged 4 years, had shown satisfactory growth and development.
Hamman-Rich Disease
Hamman and Rich (1944) described 4 adults who presented with cough and shortness of breath rapidly progressing to fatal right-sided heart failure. Postmortem pathologic examination reported 'acute diffuse interstitial fibrosis of the lung.'
After reviewing histologic material from 3 of the 4 original cases described by Hamman and Rich (1944) as well as 29 cases of their own, Olson et al. (1990) concluded that Hamman-Rich disease is an acute disorder rather than a chronic interstitial pneumonia. The patients present with the adult respiratory distress syndrome (ARDS). Of their 29 patients, 12 survived, some after long and complicated hospitalization.
Population GeneticsHunninghake et al. (2013) examined chest CT scans of 2,633 individuals enrolled in the Framingham Heart Study and found that 177 of them (7%) had interstitial lung abnormalities, and that 47 (27%) of those could be classified as fibrosis.
InheritanceMale-to-male transmission in several reported families with pulmonary fibrosis (e.g., Jacox et al., 1964; Koch, 1965; Solliday et al., 1973) suggested autosomal dominant inheritance.
PathogenesisMarshall et al. (2000) asked adult pulmonary physicians in the U.K. to identify all families under their care in which 2 or more individuals had been diagnosed with fibrosing alveolitis of unknown cause. Each proband was sent a questionnaire designed to delineate possible environmental/occupational exposures and to obtain pedigree data. They identified 25 families comprising 67 cases. Suitable data for analysis were available for 21 families (57 cases). The male:female ratio was 1.75:1 (p less than 0.05). A high resolution computed tomography scan was performed in 93% and the diagnosis of cryptogenic fibrosing alveolitis was confirmed on biopsy specimens in 32%. The mean age at diagnosis was 55.5 years. Fifty percent of cases were 'ever smokers' and 18% had been diagnosed as asthmatic. Exposure to known fibrogenic agents was recorded by 36% of patients. In no families did all affected members report the same exposure. A wide range of agents was implicated, including coal dust, wood dust, metal dust, and adhesives; the exposure was occupational in only 2 cases and in most the exposure was in the home. In 1 case there was exposure to asbestos but open lung biopsy showed typical features of cryptogenic fibrosing alveolitis and no asbestos bodies. In 1 case there was exposure to wood dust, which Hubbard et al. (1996) suggested may be a fibrogenic agent. The study demonstrated a prevalence of 1.34 cases per million in the U.K. population. Mode of inheritance was not clear. They showed 3 pedigrees in which a father and one or more children were affected. Familial cases occurred in persons younger at diagnosis but were otherwise indistinguishable from nonfamilial cases.
Gross and Hunninghake (2001) reviewed idiopathic pulmonary fibrosis, emphasizing definition, pathogenesis, diagnosis, natural history, and therapy.
Antoniou et al. (2004) provided a 'top ten list' of references pertaining to etiopathogenesis, prognosis, diagnosis, therapy, and other aspects of idiopathic pulmonary fibrosis.
Using microarray, immunohistochemical, RT-PCR, and immunoblot analyses, Wang et al. (2006) found that expression of CAV1 (601047) was significantly reduced in lung tissue and in KRT19 (148020)-positive epithelial cells, but not in CD31 (PECAM1; 173445)-positive endothelial cells, of IPF patients compared with controls. Transfer of Cav1 into mice suppressed bleomycin-induced IPF. Treatment of human pulmonary fibroblasts with TGFB (190180) decreased CAV1 mRNA and protein expression. CAV1 suppressed TGFB-induced extracellular matrix (ECM) production via the JNK (MAPK8; 601158) pathway, and it modulated SMAD (e.g., SMAD3; 603109) signaling by fibroblasts. Wang et al. (2006) concluded that CAV1 inhibits production of ECM molecules by fibroblasts and suggested that it may be a therapeutic target for IPF patients.
Alder et al. (2008) studied telomere length in 62 patients with idiopathic interstitial pneumonia (IIP), 50 (81%) of whom had been diagnosed with idiopathic pulmonary fibrosis. They found that IIP patients had shorter leukocyte telomeres compared to age-matched controls (p less than 0.0001). Screening the TERT and TERC genes in 100 consecutive patients, including the 62 individuals in whom telomere length had been measured, revealed a mutation in TERC in only 1 patient (602322.0010). The authors noted that a subset of patients (10%) with no family history and no detectable mutations in telomerase had telomere lengths in the range of known mutation carriers. The presence of individuals with very short telomeres suggested the presence of other genetic mechanisms that can lead to telomere shortening. From a total of 150 IIP patients, Alder et al. (2008) detected a cluster of 4 (3%) IPF patients who also had cryptogenic liver cirrhosis, suggesting that the observed telomere shortening has consequences and can contribute to what appears clinically as 'idiopathic' progressive organ failure in the lung and the liver.
In a bleomycin-induced mouse model of pulmonary fibrosis, Oga et al. (2009) demonstrated that loss of prostaglandin F receptor (PTGFR; 600563) selectively attenuated pulmonary fibrosis while maintaining levels of alveolar inflammation and TGFB stimulation similar to those of wildtype mice, and that PTGFR deficiency and inhibition of TGFB signaling additively decreased fibrosis. PGF(2-alpha) was found to be abundant in bronchoalveolar lavage fluid from patients with idiopathic pulmonary fibrosis; in addition, PGF(2-alpha) stimulated proliferation and collagen production of lung fibroblasts via PTGFR independently of TGFB. Oga et al. (2009) concluded that PTGFR signaling facilitates pulmonary fibrosis independently of TGFB.
MappingWang et al. (2009) performed whole-genome linkage analysis in 29 members of a 4-generation family segregating autosomal dominant idiopathic pulmonary fibrosis with or without lung cancer (see 211980) and obtained a model-free lod score of 3.22 on chromosome 10. All affected family members shared an identical-by-descent region on chromosome 10 between markers rs877783 and rs4869, a 15.7-Mb interval containing 118 annotated genes.
Molecular GeneticsMutation in the SFTPA2 Gene
In a 4-generation family segregating autosomal dominant IPF with or without lung cancer mapping to chromosome 10, Wang et al. (2009) sequenced the candidate genes SFTPA1 (178630) and SFTPA2 (178642) and identified heterozygosity for a missense mutation in SFTPA2 (178642.0001) that segregated with disease. SFTPA1 and SFTPA2 were then sequenced in 58 additional IPF probands, and a heterozygous missense mutation in SFTPA2 (178642.0002) was identified in a 45-year-old man with IPF and lung cancer. The patient reported multiple family members over 3 generations with undefined lung disease, pulmonary fibrosis, and/or lung cancer, but they were not available for study. Neither mutation was found in 3,557 population-based controls, and transfection studies showed that the mutant proteins are retained in the endoplasmic reticulum and are not secreted.
Association with MUC5B
Using a genomewide linkage scan, Seibold et al. (2011) detected linkage between idiopathic interstitial pneumonia and a 3.4-Mb region of chromosome 11p15 in 82 families. They found association of the minor allele (T) of a single-nucleotide polymorphism (SNP) in the promoter of the MUC5B gene, rs35705950 (600770.0001), with idiopathic pulmonary fibrosis (allelic association, p = 2.5 x 10(-37)) and with familial interstitial pneumonia (allelic association p = 1.2 x 10(-15)). MUC5B expression in the lung was 14.1 times as high in subjects who had idiopathic pulmonary fibrosis as in those who did not (P less than 0.001). The variant allele of rs35705950 was associated with upregulation in MUC5B expression in the lung in unaffected subjects (expression was 37.4 times as high as in unaffected subjects homozygous for the wildtype allele, P less than 0.001). MUC5B protein was expressed in lesions of idiopathic pulmonary fibrosis.
In a study of 341 cases with idiopathic pulmonary fibrosis from the University of Pittsburgh and the University of Chicago and 802 controls from the same 2 centers, Zhang et al. (2011) confirmed the findings of Seibold et al. (2011), finding strong association of the minor allele at rs35705950 with pulmonary fibrosis (P = 7.6 x 10(-40)).
Association with the Major Histocompatibility Complex
Falfan-Valencia et al. (2005) evaluated polymorphisms of the major histocompatibility complex (MHC; see 142800) on chromosome 6q21 in a cohort of 75 IPF patients and 95 controls. In addition, they examined the effect of bronchoalveolar lavage (BAL) from IPF patients with different MHC haplotypes. They reported findings suggesting that some MHC polymorphisms confer susceptibility to IPF and suggested that this susceptibility might be related to the induction of epithelial cell apoptosis, a critical process in the development of the disease.
Aquino-Galvez et al. (2009) analyzed the MICA gene (600169) in 80 sporadic IPF patients and 201 controls and found a significant increase of MICA*001 in the IPF cohort (odds ratio, 2.91; corrected p = 0.03). In addition, the MICA *001/*00201 genotype was significantly increased in patients with IPF compared with healthy controls (odds ratio, 4.72; corrected p = 0.01). Strong immunoreactive MICA staining was localized in alveolar epithelial cells and fibroblasts from IPF lungs, whereas control lungs were negative. Soluble MICA was detected in 35% of IPF patients compared to 12% of control subjects (p = 0.0007). The expression of the MICA receptor NKG2D (KLRK1; 611817) was significantly decreased in gamma/delta T cells and natural killer cells obtained from IPF lungs. Aquino-Galvez et al. (2009) concluded that MICA polymorphisms and abnormal expression of NKG2D might contribute to IPF susceptibility.
Associations Pending Confirmation
Selman et al. (2003) studied 84 unrelated patients with idiopathic pulmonary fibrosis. All patients presented with progressive dyspnea and cough, predominantly basal inspiratory crackles, radiographic bilateral interstitial opacities, high resolution computed tomography scan patterns with varying degrees of reticular infiltrates, subpleural and basal honeycombing, and sparse ground-glass opacification. All patients showed significant reduction in lung volumes and hypoxemia at rest that worsened with exercise. Among 54 nonsmokers, they found an association between an allele of the SPA1 gene, designated 6A(4) (178630.0001), and pulmonary fibrosis. This polymorphism was associated with idiopathic pulmonary fibrosis in nonsmokers but not in smokers.
Hodgson et al. (2006) performed a genomewide scan in 6 multiplex families with familial idiopathic pulmonary fibrosis who originated from southeastern Finland. Most Finnish multiplex families were clustered in that geographic region, and the population history suggested that the clustering might be explained by an ancestor shared among the patients. The genomewide scan identified 5 loci of interest. A shared haplotype on 4q31 was significantly more frequent among the patients than in population-based controls. The shared haplotype harbored 2 functionally uncharacterized genes, ELMOD2 (610196) and LOC152586 (610310), of which only ELMOD2 was expressed in lung and showed significantly decreased mRNA expression in lung from idiopathic pulmonary fibrosis when compared with that of healthy lung. The results suggested that ELMOD2 may be a candidate gene for susceptibility to familial IPF.
Animal ModelTo examine the possibility that the fibroblasts involved in pulmonary fibrosis are of extrapulmonary origin and derived from bone marrow progenitor cells, Hashimoto et al. (2004) produced adult mice durably engrafted with bone marrow isolated from transgenic mice expressing enhanced GFP. Induction of pulmonary fibrosis in these chimeric mice by endotracheal bleomycin (BLM) injection caused large numbers of GFP+ cells to appear in active fibrotic lesions, whereas only a few GFP+ cells could be identified in control lungs. Flow cytometric analysis of lung cells confirmed the increase and revealed significant increase in GFP+ cells that also expressed type I collagen (see 120150).
Fibrocytes present in the peripheral circulation were first identified by Bucala et al. (1994). These cells comprised a minor component of the circulating pool of leukocytes (less than 1%) and expressed a characteristic pattern of markers, including collagen I and CD45 (151460). When cultured in vitro, these cells became adherent and developed a spindle-shaped morphology. Subsequent studies showed that these circulating fibrocytes express chemokine receptors such as CXCR4 (162643) and CCR7 (600242). Pulmonary fibrosis was originally thought to be mediated solely by resident lung fibroblasts. Phillips et al. (2004) showed that a population of human circulating fibrocytes positive for CD45, type I collagen, and CXCR4 migrates in response to CXCL12 (600835) and traffics to the lungs in a murine model of bleomycin-induced pulmonary fibrosis. They demonstrated that murine fibrocytes of this type also traffic to the lungs in response to a bleomycin challenge. Maximal intrapulmonary recruitment of these fibrocytes directly correlated with increased collagen deposition in the lungs. Treatment of bleomycin-exposed animals with specific neutralizing anti-CXCL12 antibodies inhibited intrapulmonary recruitment of circulating fibrocytes of this type and attenuated lung fibrosis. Thus, Phillips et al. (2004) demonstrated that circulating fibrocytes contribute to the pathogenesis of pulmonary fibrosis.
Imai et al. (2005) reported that ACE2 (300335) and the angiotensin II type 2 receptor (300034) protect mice from severe acute lung injury induced by acid aspiration or sepsis. However, other components of the renin-angiotensin system, including ACE (106180), angiotensin II (see 106150), and the angiotensin II type 1a receptor (106165), promote disease pathogenesis, induce lung edemas, and impair lung function. Imai et al. (2005) showed that mice deficient for ACE show markedly improved disease, and also that recombinant ACE2 can protect mice from severe acute lung injury. Imai et al. (2005) concluded that their data identified a critical function for ACE2 in acute lung injury.
Tager et al. (2008) found elevated levels of the lysolipid mediator lysophosphatidic acid (LPA) in bronchoalveolar lavage (BAL) fluid from mice following lung injury in the bleomycin model of pulmonary fibrosis. In mice lacking the LPA receptor Edg2 (602282), both accumulation of fibroblasts and vascular leak induced by bleomycin challenge were markedly attenuated compared to wildtype mice, whereas leukocyte recruitment was preserved during the first week after injury. In BAL fluid from patients with idiopathic pulmonary fibrosis, LPA levels were also increased, and inhibition of EDG2 markedly reduced fibroblast responses to the chemotactic activity of BAL fluid. Tager et al. (2008) concluded that the LPA-EDG2 pathway mediates both excessive accumulation of fibroblasts and persistent vascular leak that have been implicated in pulmonary fibrosis.