Transcript SP-A - e

Surfactant Composition and Function
Joanna Floros, Ph.D
Evan Pugh Professor, Departments of Cellular
and Molecular Physiology, Pediatrics, and
Obstetrics and Gynecology.
The Pennsylvania State University,
College of Medicine, Hershey, PA,
U.S.A
8th World Hellenic Biomedical Congress
Surfactant
1. Characteristics of Surfactant
•
•
•
•
What is surfactant?
What is its composition?
Where is it made?
What is its structure?
2. Function of surfactant
What is Pulmonary Surfactant and
What is its Composition?
Pulmonary surfactant biochemically, is a lipoprotein complex
that lines the internal surface of the alveoli.
MAJOR CONSTITUENTS OF PULMONARY SURFACTANT
Unsaturated
PC
PC
(DSPC)
PE
16:/16:0
Protein
Other lipids
Cholesterol
PG PI
Surfactant
SP-A
SP-B
SP-C
SP-D
Other
Proteins
Proteins
Fishman 2-19
SURFACTANT HETEROGENEITY AND LIFE CYCLE
LAMELLAR BODIES
TUBULAR
MYELIN
SP-A
SURFACE FILM
LARGE AGGREGATES
LB, TM, SP-A
SMALL AGGREGATES
HYPOPHASE FLUID
(SUPERNATANT)
Surfactant
1. Characteristics of Surfactant
•
•
•
•
What is surfactant?
What is its composition?
Where is it made?
What is its structure?
2. Function of surfactant and/or surfactant components
• Lowering of surface tension.
• Innate host defense.
• Initiation of parturition (SP-A, a hormone?)
Functions of surfactant
Surface tension
• Stabilizes alveoli and prevents alveolar (lung) collapse
with each exhalation by lowering the surface tension at
the air-liquid surface.
Host defense
• Surfactant components play a role in host defense and
protect the lung from injuries or infections caused by inhaled
microorganisms, particles, toxins, other.
Initiation of labor
• One of the protein component of surfactant (SP-A) may
serve as a hormone in parturition.
Air-Liquid Interface
Without surfactant
With surfactant
Surfactant
J. Kending
MAJOR CONSTITUENTS OF PULMONARY SURFACTANT
Unsaturated
PC
PC
(DSPC)
PE
16:0/16:0
Protein
Other lipids
Cholesterol
PG PI
Surfactant
SP-A
SP-B
SP-C
SP-D
Other
Proteins
Proteins
Functions of surfactant
Surface tension
• Stabilizes alveoli and prevents alveolar (lung) collapse with
each exhalation by lowering the surface tension at the airliquid surface.
Host defense
• Surfactant components play a role in host defense and
protect the lung from injuries or infections caused by
inhaled microorganisms, particles, toxins, other.
Initiation of labor
• One of the protein component of surfactant (SP-A) may
serve as a hormone in parturition.
SURFACTANT REGULATION OF IMMUNE CELLS
PE
SM
CHOL
SP-A
SP-A
Stimulation
LIPID
PI
PG
PC
Inhibition
STIMULATION
Oxidant Production
Splenocyte Proliferation
Cell Surface Markers
Cytokine Production
NF-kB Activation
Fibroblast Apoptosis
Collagen and Collagenase
Production
PI
PG
PC
PE
SM
CHOL
SP-A
STIMULATION
INHIBITION
INHIBITION
SP-A FUNCTION
Surfactant-related
Host defense-related
Innate Immunity
SP-A
Innate
800 700
TUBULAR
MYELIN
LARGE
AGGREGATES
600
myr
Adaptive
500
present
Regulation of inflammatory
processes
Cell Surface Markers;
Cytokine Production;
NF-kB Activation;
Collagen and Collagenase
Production
Human SP-A Genes, and Variants
Genes
Variants
C
SP-A2
SP-A1
P
1A0
T
6A2
The above variants have been shown to exhibit qualitative and
quantitative differences.
In addition environmental insults, such as ozone, appear to
differentially alter their functional activity and thus contribute to
individual differences in disease susceptibility.
Differences exist among SP-A variants in their ability
to enhance phagocytosis of bacteria by alveolar
macrophages in the presence or absence of environmental
factors.
EXPERIMENTAL APPROACH
agar plate
suspension
of bacteria
ozone
BAL
wash off free
bacteria
insect cells or
mammalian cells
SP-A
phagocytosis
rat
alveolar macrophages
slide
preparation
light
microscopy
analysis
RESULTS
Microscopic view of live P. aeruginosa, phagocytized by rat alveolar
macrophages in the presence or absence of human SP-A
No SP-A
SP-A
SP-A2 products exhibit higher phagocytic ability than SP-A1
Mammalian expressed variants
***
Phagocytic index (%)
500
*
400
*
hSP-A
300
SP-A2
200
100
SP-A1
1A0
1A
1.56 mg/ml
* SP-A2 vs. SP-A1 ;
§
**
6A2
6A4
n=5
** 6A2 vs. 6A4 ; *** hSP-A vs. 6A4 (mammalian); (hSP-A: 25 µg/ml)
hSP-A vs. SP-A variants (insect)
Bacteria: P.aeruginosa
Phagocytic index: % of bacteria-positive AMs  the average # of bacteria per bacteria-positive AMs
Mikerov et al
Ability of SP-A variants to enhance phagocytosis by
alveolar macrophages following exposure to ozone.
Unexposed
Ozone-exposed
1A0
>
6A4
=
1A0/6A4 >
1A0
6A4
1A0/6A4
(SP-A2)
(SP-A1)
(SP-A2/SP-A1)
Functions of surfactant
Surface tension
• Stabilizes alveoli and prevents alveolar (lung) collapse with
each exhalation by lowering the surface tension at the airliquid surface.
Host defense
• Surfactant components play a role in host defense and
protect the lung from injuries or infections caused by inhaled
microorganisms, particles, toxins, other.
Initiation of labor
• One of the protein component of surfactant (SP-A) may
serve as a hormone in parturition.
Fetal SP-A initiates labor
Increased levels of SP-A
activate
Surfactant lipids
Fetal macrophages
(Arachidonate derivatives)
Increased levels of proinflammatory cytokines
(i.e. IL-b1)
Prostaglandin synthesis
activate
NF-kB
Increase expression of genes that
cause myometrial contractibility
P65 antagonizes progesterone receptor
activation of genes that modulate
uterine quiescence.
Summary
• Pulmonary surfactant, a lipoprotein complex, is essential
throughout life for normal lung function, host defense, and other
functions.
• Derangement in surfactant either through alterations in
composition or modification (i.e. oxidation) can negatively affect
normal lung function and host defense.
• Genetic differences in surfactant components may contribute to
differences in disease risk among individuals.