Transcript Defense Mechanisms and Immunology

Defense Mechanisms and
Immunology
• 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.
• 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
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
• 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
• SP-A–deficient mice are more susceptible to
infection by :
• group B Streptococcus,
• Pseudomonas aeruginosa,
• Haemophilus influenza,
• respiratory syncytial virus,
• Pneumocystis carinii.
Bacteria
• SP-A binds to and increases phagocytosis of
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.
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.
• 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
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.
• annual severity of influenza infections is related
to their ability to bind to SP-D : strains with less
SP-D binding are more virulent.
Innate Immunity in the Lungs
• 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
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
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.
• 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.
• 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
• 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.