Extensive phenotyping of individuals at risk for familial interstitial pneumonia reveals clues to the pathogenesis of interstitial lung disease.
BACKGROUND
Asymptomatic relatives of patients with familial interstitial pneumonia (FIP), the inherited form of idiopathic interstitial pneumonia, carry increased risk for developing interstitial lung disease.


OBJECTIVE
Studying these at-risk individuals provides a unique opportunity to investigate early stages of FIP pathogenesis and develop predictive models of disease onset.


METHODS
Seventy-five asymptomatic first-degree relatives of FIP patients (mean age, 50.8 yr) underwent blood sampling and high-resolution chest computed tomography (HRCT) scanning in an ongoing cohort study; 72 consented to bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsies. Twenty-seven healthy individuals were used as control subjects.


RESULTS
Eleven of 75 at-risk subjects (14%) had evidence of interstitial changes by HRCT, whereas 35.2% had abnormalities on transbronchial biopsies. No differences were noted in inflammatory cells in BAL between at-risk individuals and control subjects. At-risk subjects had increased herpesvirus DNA in cell-free BAL and evidence of herpesvirus antigen expression in alveolar epithelial cells (AECs), which correlated with expression of endoplasmic reticulum stress markers in AECs. Peripheral blood mononuclear cell and AEC telomere length were shorter in at-risk individuals than healthy control subjects. The minor allele frequency of the Muc5B rs35705950 promoter polymorphism was increased in at-risk subjects. Levels of several plasma biomarkers differed between at-risk subjects and control subjects, and correlated with abnormal HRCT scans.


CONCLUSIONS
Evidence of lung parenchymal remodeling and epithelial dysfunction was identified in asymptomatic individuals at risk for FIP. Together, these findings offer new insights into the early pathogenesis of idiopathic interstitial pneumonia and provide an ongoing opportunity to characterize presymptomatic abnormalities that predict progression to clinical disease.
1 Division of Allergy, Pulmonary and Critical Care Medicine and.
Jonathan A
JA
Kropski
Jason M
JM
Pritchett
Donald F
DF
Zoz
Peter F
PF
Crossno
Cheryl
C
Markin
Errine T
ET
Garnett
Amber L
AL
Degryse
Daphne B
DB
Mitchell
Vasiliy V
VV
Polosukhin
Otis B
OB
Rickman
Leena
L
Choi
Dong-Sheng
DS
Cheng
Melinda E
ME
McConaha
Brittany R
BR
Jones
Linda A
LA
Gleaves
Frank B
FB
McMahon
John A
JA
Worrell
Joseph F
JF
Solus
Lorraine B
LB
Ware
Jae Woo
JW
Lee
Pierre P
PP
Massion
Rinat
R
Zaynagetdinov
Eric S
ES
White
Jonathan D
JD
Kurtis
Joyce E
JE
Johnson
Steve D
SD
Groshong
Lisa H
LH
Lancaster
Lisa R
LR
Young
Mark P
MP
Steele
John A
JA
Phillips Iii
Joy D
JD
Cogan
James E
JE
Loyd
William E
WE
Lawson
Timothy S
TS
Blackwell
D000328:Adult; D000368:Aged; D058070:Asymptomatic Diseases; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D018893:Bronchoalveolar Lavage; D001999:Bronchoscopy; D016022:Case-Control Studies; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D005787:Gene Frequency; D005819:Genetic Markers; D006564:Herpesviridae / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D008168:Lung / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000821:virology; D017563:Lung Diseases, Interstitial / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000821:virology; D008297:Male; D008875:Middle Aged; D055257:Mucin-5B / Q000235:genetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D014057:Tomography, X-Ray Computed
D015415:Biomarkers; D004279:DNA, Viral; D005819:Genetic Markers; C524578:MUC5B protein, human; D055257:Mucin-5B
IPF; alveolar epithelial cell; biomarker; bronchoscopy; telomere