Segmental Allergen Challenge Alters Multimeric Structure and Function of Surfactant Protein D in Humans

Abstract

Rationale: Surfactant protein D (SP-D), a 43-kD collectin, is synthesized and secreted by airway epithelia as a dodecamer formed by assembly of four trimeric subunits. We have previously shown that the quaternary structure of SP-D can be altered during inflammatory lung injury through its modification by S-nitrosylation, which in turn alters its functional behavior producing a proinflammatory response in effector cells. Objectives: We hypothesized that alterations in structure and function of SP-D may occur in humans with acute allergic inflammation. Methods: Bronchoalveolar lavage (BAL) fluid was collected from 15 nonsmoking patients with mild intermittent allergic asthma before and 24 hours after segmental provocation with saline, allergen, LPS, and mixtures of allergen and LPS. Structural modifications of SP-D were analyzed by native and sodium dodecyl sulfate gel electrophoresis. Measurements and Main Results: The multimeric structure of native SP-D was found to be disrupted after provocation with allergen or a mixture of allergen and LPS. Interestingly, under reducing conditions, sodium dodecyl sulfate-polyacrylamide gel electrophoresis demonstrated that 7 of 15 patients with asthma developed an abnormal cross-linked SP-D band after segmental challenge with either allergen or a mixture of allergen with LPS but not LPS alone. Importantly, patients with asthma with cross-linked SP-D demonstrated significantly higher levels of BAL eosinophils, nitrogen oxides, IL-4, IL-5, IL-13, and S-nitrosothiol-SP-D compared with patients without cross-linked SP-D. Conclusions: We conclude that segmental allergen challenge results in changes of SP-D multimeric structure and that these modifications are associated with an altered local inflammatory response in the distal airways.

Impact of Surfactant Protein D, Interleukin-5, and Eosinophilia on Cryptococcosis

“…Conversely, SP-D can act as a proinflammatory molecule leading to NF-B activation and proinflammatory signaling cascades after S-nitrosylation, trimer formation, and interaction with CD91/calreticulin (47). Previous work showing that oligomeric SP-D inhibits eosinophil chemotaxis, while S-nitrosylated SP-D does not, supports this dual-role paradigm for SP-D in eosinophilia (48,49). Future studies should focus on gaining a deeper understanding of the dual role of SP-D in infection and inflammation by examining the oligomeric structure and posttranslational modifications of SP-D during both C. neoformans and A. fumigatus infections.…”

Nitrosothiols in Bacterial Pathogens and Pathogenesis

“…Reduction of SNO-BAL with ascorbate ablated this effect and permitted the formation of dodecamers, which bind to SIRP-a and block pro-inflammatory signaling (42). These findings have subsequently been corroborated in vivo (5,6). For a more in-depth review of the S-nitrosylation of SP-D, see Ref.…”

“…These include alkyl hydroperoxide reductase (TsaA) and the urease alpha subunit (UreA), 6 LAVER ET AL.…”

Eosinophil-Associated Lung Diseases. A Cry for Surfactant Proteins A and D Help?

“…Modification of SP-D oligimerization and Tyr crosslinking have been investigated in the context of allergic asthma (126). SP-D in BAL fluid collected from subjects with asthma before and after allergen challenge or the combination of allergen and LPS challenge had increases in both monomeric and in tyrosine-crosslinked SP-D.…”