title: Role of defensins in the pathogenesis of chronic lung allograft rejection.
abstract: Chronic rejection predominantly manifested as bronchiolitis obliterans syndrome (BOS), still remains a major problem affecting long-term outcomes in human lung transplantation (LTx). Donor specific antibodies (DSA) and infiltration of neutrophils in the graft have been associated with the development of BOS. This study determines the role of defensins, produced by neutrophils, and its interaction with α-1-antitrypsin (AAT) towards induction of airway inflammation and fibrosis which are characteristic hallmarks of BOS. Bronchoalveolar lavage (BAL) and serum from LTx recipients, BOS+ (n=28), BOS- (n=26) and normal healthy controls (n=24) were analyzed. Our results show that BOS+ LTx recipients had higher α-defensins (HNP1-3) and β-defensin2 HBD2 concentration in BAL and serum compared to BOS-DSA-recipients and normal controls (p=0.03). BOS+ patients had significantly lower serum AAT along with higher circulating concentration of HNP-AAT complexes in BAL (p=0.05). Stimulation of primary small airway epithelial cells (SAECs) with HNPs induced expression of HBD2, adhesion molecules (ICAM and VCAM), cytokines (IL-6, IL-1β, IL-13, IL-8 and MCP-1) and growth-factor (VEGF and EGF). In contrast, anti-inflammatory cytokine, IL-10 expression decreased 2-fold (p=0.002). HNPs mediated SAEC activation was completely abrogated by AAT. In conclusion, our results demonstrates that neutrophil secretory product, α-defensins, stimulate β-defensin production by SAECs causing upregulation of pro-inflammatory and pro-fibrotic signaling molecules. Hence, chronic stimulation of airway epithelial cells by defensins can lead to inflammation and fibrosis the central events in the development of BOS following LTx.
authors.affiliation: Department of Surgery, Washington University School of Medicine, Saint Louis, MO 63110, United States; Department of Biological Sciences, Tennessee State University, Nashville, TN 37209, United States.
authors.forename: Venkataswarup
authors.initials: V
authors.lastname: Tiriveedhi
authors.affiliation: Department of Surgery, Washington University School of Medicine, Saint Louis, MO 63110, United States.
authors.forename: Babak
authors.initials: B
authors.lastname: Banan
authors.affiliation: Department of Surgery, Washington University School of Medicine, Saint Louis, MO 63110, United States.
authors.forename: Saini
authors.initials: S
authors.lastname: Deepti
authors.affiliation: Department of Surgery, Washington University School of Medicine, Saint Louis, MO 63110, United States.
authors.forename: Angaswamy
authors.initials: A
authors.lastname: Nataraju
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, Saint Louis, MO 63110, United States.
authors.forename: Ramsey
authors.initials: R
authors.lastname: Hachem
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, Saint Louis, MO 63110, United States.
authors.forename: Elbert
authors.initials: E
authors.lastname: Trulock
authors.affiliation: Department of Cardiothoracic Surgery, Washington University School of Medicine, Saint Louis, MO 63110, United States.
authors.forename: Patterson G
authors.initials: PG
authors.lastname: Alexander
authors.affiliation: Department of Surgery, Washington University School of Medicine, Saint Louis, MO 63110, United States; Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, United States. Electronic address: kumart@wustl.edu.
authors.forename: Mohanakumar
authors.initials: M
authors.lastname: Thalachallour
mesh_terms: D001989:Bronchiolitis Obliterans / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism; D002908:Chronic Disease; D016207:Cytokines / Q000378:metabolism; D023082:Defensins / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D016040:Lung Transplantation / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D013577:Syndrome; D000515:alpha 1-Antitrypsin / Q000378:metabolism; D023084:alpha-Defensins / Q000737:chemistry / Q000378:metabolism; D023083:beta-Defensins / Q000737:chemistry / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016207:Cytokines; D023082:Defensins; D000515:alpha 1-Antitrypsin; D023084:alpha-Defensins; D023083:beta-Defensins