Defense Mechanisms and Immunology

1. Defense Mechanisms and Immunology

2. Pulmonary surface-active material (surfactant) allows one to breathe effortlessly. • In the absence of surfactant, the work of breathing may increase from less than 2% to more than 10% of total oxygen consumption.

3. Surfactant provides the low surface tension at the air-liquid interface that is necessary to prevent atelectasis, alveolar flooding, and severe hypoxia. • surfactant is also important for maintaining the patency of small airways

5. Surfactant Protein A • SP-A is not essential for normal metabolism and processing of surfactant in vivo • The major function of SP-A appears to be in innate immunity, in which • SP-A binds to a variety of microorganisms, • promotes their clearance by phagocytic cells, • and directly alters the function of immune effector cells

6. In humans, almost all the SP-A is found in the alveoli, • there is SP-A in human tracheal submucosal glands • low-level expression in some nonpulmonary tissues

7. SP-A–deficient mice are more susceptible to infection by : • group B Streptococcus, • Pseudomonas aeruginosa, • Haemophilus influenza, • respiratory syncytial virus, • Pneumocystis carinii.

8. Bacteria • SP-A binds to and increases phagocytosisof Streptococcus pneumoniae, group A Streptococcus, and Staphylococcus aureus. • isolated SP-A binds to and increases the phagocytosis of H. influenzae, Klebsiella, and P. aeruginosa. • SP-A and SP-D could directly kill gram-negative bacteria by increasing their membrane permeability.

9. Mycobacteria, Fungi, Mycoplasma, and Pneumocystis. • SP-A enhances the adherence and subsequent phagocytosis of mycobacteria by macrophages. • SP-A bound to Aspergillus fumigatus conidia and enhanced their phagocytosis and killing by human neutrophils and alveolar macrophages. • SP-A could directly kill extracellular, but not intracellular, Histoplasma.

10. SP-A appears to suppress the secretion of inflammatory cytokines by macrophages in the normal lung but enhances cytokine production during infection or lung injury. (inflammatory paradox of SP-A) • SP-A has also been shown to bind to apoptotic cells and to increase their uptake and removal by macrophages

11. Surfactant Protein D • SP-D is a calcium-dependent lectin and an important component of innate immunity • The knockout mouse shows an accumulation of large foamy macrophages with excess metalloprotease activity  alveolar wall destruction and subsequent air space enlargement • susceptible to infection with influenza A virus and Aspergillus.

12. annual severity of influenza infections is related to their ability to bind to SP-D : strains with less SP-D binding are more virulent.

13. Innate Immunity in the Lungs

16. anatomic structure and epithelial cell lineages of the tracheobronchial tree • particles in excess of 10 µm in diameter are deposited on the mucus-coated surfaces of the nose, pharynx, trachea,descending airways

17. Epithelium • The classic antimicrobial defense mechanism in the conducting airways is the mucociliary system, which moves microbes deposited on the airway epithelial surface upward and out of the lungs • major antibacterial components include • lysozyme, • lactoferrin, • β-defensins

18. Neutrophils • PMNs serve as the immediate effector arm of the innate immune system • the pulmonary capillaries slow the transit of PMNs because of the small cross-sectional capillary diameter.This produces a reservoir of capillary PMNs that are poised to respond directly to signals from the innate immune system in the air spaces.

19. Once in the air spaces, PMNs ingest bacteria and fungi that have been opsonized by complement and immunoglobulins that accumulate in the air spaces at sites of inflammation. • PMNs contain a series of effector mechanisms to kill bacteria and fungi: • oxidant production, • microbicidal proteins in primary azurophilic granules, • extracellular traps.

20. When defensins are added to the phagolysosomal space, they attach to negatively charged microbial membranes via electrostatic interactions and are thought to form lytic pores in the microbial cell wall. • at sites of intense inflammation, PMNs release superoxide anion, H2O2, and granular contents directly into the extracellular environment, leading to oxidant formation in the alveolar spaces

21. PMNs can project uncoiled nuclear DNA into the surrounding environment to form NETs (neutrophil extracellular traps) that ensnare and destroy bacteria • NET formation depends on the initial respiratory burst of the PMN and leads to the death of the PMN in a process that is distinct from apoptosis and necrosis.