Major histocompatibility complex and alveolar epithelial apoptosis in idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterized by fibroblast expansion, and tissue remodeling. It is considered a multifactorial disease but the possible involved genes are largely unknown. Interestingly, studies regarding the possible role of major histocompatibility complex (MHC) are scanty and show contradictory results. In this study, we evaluated the polymorphisms of the MHC, locus HLA-B, -DRB1, and -DQB1 in a cohort of 75 IPF patients and 95 controls by using PCR and hybridization with sequence-specific oligonucleotide probes. In addition, we examined the effect of bronchoalveolar lavage (BAL) from IPF patients with different MHC haplotypes on alveolar epithelial growth rate by WST-1 cell viability assay and on epithelial apoptosis by flow cytometry and by cleaved caspase-3 in cell homogenates. Three haplotypes were significantly increased in IPF: (1) HLA-B*15-DRB1*0101-DQB1*0501 (OR=10.72, CI=1.43-459.6; pC=0.011); (2) HLA-B*52-DRB1*1402-DQB1*0301 (OR=4.42, CI=1.21-24.1; pC=0.024); and (3) HLA-B*35-DRB1*0407-DQB1*0302 (OR=4.73, CI=1.53-19.5; pC=0.005). BAL from patients with the later haplotype significantly reduced epithelial growth rate ( approximately 30%) and caused epithelial cell apoptosis assayed by cleaved caspase-3 (351.7+/-16.5 pg/10(6) cells versus 264+/-24 from controls, and 274+/-36.8 and 256.5+/-10.7 from the other haplotypes; P<0.05), and DNA breaks labeling by flow cytometry (23.7+/-6.9% versus 3.1+/-0.7% from controls, and 6.5+/-0.6% and 7.6+/-1.2% from the other two haplotypes; P<0.01). These findings suggest that some MHC polymorphisms confer susceptibility to IPF, which might be related with the induction of epithelial cell apoptosis, a critical process in the development of the disease.
Falfán-Valencia
Ramcés
R
Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502, CP 14080, México DF, Mexico.
Camarena
Angel
A
Juárez
Armida
A
Becerril
Carina
C
Montaño
Martha
M
Cisneros
José
J
Mendoza
Felipe
F
Granados
Julio
J
Pardo
Annie
A
Selman
Moisés
M
D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000235:genetics*; D001992:Bronchoalveolar Lavage Fluid; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D011650:Pulmonary Alveoli / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D020545:Respiratory Mucosa / Q000201:enzymology / Q000473:pathology
D006680:HLA Antigens; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases