True or False: The lung is the largest epithelial surface in the body
Chronic disease states can happen due to two general things. What are they?
1. Infection overwhelms the system (e.g. tuberculosis) 2. Pathologic responses are over exuberant and impair rather than protect the host.
What are the 3 pulmonary defense mechanisms?
1. Configuration of the nasopharynx and serial branching of the airways allows for particle deposition proximal to more vulnerable alveolar structures. 2. Mucociliary clearance and cough 3. Alveolar clearance (macrophages and immune response)
Mucus is hydrated by ____ ____
What are constituents of airway epithelial fluid that help with defense, maintanance of structure and function?
- Antimicrobial peptides and proteins (e.g. B-defensins, cathelicidin, lysozyme, and lactoferrin)
- Antioxidants (glutathione)
- Decreased pH
____ of mucus plays an important role in the pathophysiologic characteristics of various chronic airway diseases
What are 3 things that can reduce ciliary function?
1. air pollution
2. viral infection
What is the genetic disorder associated with abnormal ciliary function?
Primary ciliary dyskinesia (immotile ciliary syndrome)
- autosomal recessive
- due to defects in dynein arms (a motor control protein that helps with cytoskeleton movement of cilia)
- these patients have sinusitis, bronchiectasis, situs inversus (mirrored organs), and pneumonia
- Kartagener's syndrome which is a combination of situs inversus, chronic sinusitis, and bronchiectasis.
True or False: The hydration of mucus is very important.
True. CF patients are unable to properly hydrate their mucus so it gets thick and difficult to move.
What is a common feature of cystic fibrosis, chronic bronchitis, and asthma?
A. Dysfunctional cilia
B. Increased mucus secretion
C. Defects in ion transport
D. Caused by smoking
B. Increased mucus secretion
What do dendritic cells do in the defense mechanism?
They traffic inhaled particles to local lymph nodes to promote tolerance to common antigens
What's the cell breakdown in a normal person's alveolar air spaces?
Lymphocytes (less than 5%)
Eosinophils (less than 1 %)
Neutrophils (less than 1 %)
Smokers have a dramatic ____ in the number of alveolar macrophages
Which of the following is the predominant cell type in the bronchoalveolar lavage of normal subjects?
In the absence of PAMPS, what happens to inhaled particles?
Particles are taken in by dendritic cells and taken to local lymph nodes to promote tolerance to common antigens. In the alveolar spaces, macrophages take up the inhaled particles to try to maintain an anti-inflammatory state.
How is inflammation suppressed in the absence of PAMPs?
Inflammation is suppressed through the tonic signaling of resident alveolar macrophages via SIRPalpha (signal inhibitory regulatory protein).
Surfactant proteins A and D (a.k.a. collectins) bind to SIRPalpha which blocks downstream signaling cascade of inflammation.
What are secreted pattern recognition receptors?
They serve as bridges between PAMPs and their specific receptors.
This includes collectins (SP-A, SP-D), complement (recognizes Fc region on IgG and IgM antibodies--promotes opsonization of microbes), and pentraxins (c-reactive protein, serum amyloid)
What are cellular pattern recognition receptors? Name 3 categories
These sense PAMPs in extracellular, endosomal, and cytoplasmic compartments.
- Toll-like receptors (Expressed on epithelial cells, macrophages, PMNs and dendritic cells)
- Scavenger receptors (CD36, CD206)
- C-type lectin receptors (recognize high density carbohydrate based PAMPs)
What happens when PAMPs are present in inhaled material?
- Activation of innate immunity
- Stimulation of epithelial cells to express chemokines, cytokines, and lipid mediators
- Recruitment of neutrophils
- Dendritic cells traffic to lymph nodes and stimulate T-cell proliferation
- Alveolar macrophages initiate inflammation
What do SP-A and SP-D in presence of PAMPs?
Instead of being bound to the inhibitory proteins, SP-A and SP-D are secreted and bind to microbial PAMPs leading to opsonization and phagocytosis by alveolar macrophages and dendritic cells. They also initiate the inflammatory response.
What is a common chemotactic factor that attracts neutrophils?
In an inflammatory response, how are neutrophils attracted to the lung?
Alveolar macrophages and epithelium release IL-8 which recruits neutrophils.
What do neutrophils do once they arrive in the lung?
They ingest bacteria and fungi that have been opsonized by complement. They kill by oxidant production, microbial-cidal proteins, and extracellular traps
Macrophages perform many different roles in pulmonary defense. Name 4 roles
- Suppression of pro-inflammatory adaptive immune responses (when no PAMPs are around)
- Clearance of particles, pathogens, apoptotic cells, and cellular debris
- Elicit an inflammatory response when appropriate (presence of PAMPs)
- Induction of tissue repair
True or False: You are born with resident macrophages in your lung that developed from the yolk sac and liver.
During inflammation, the level of resident macrophages remains steady while the number of macrophages increases and decreases based on the monocytes being recruited to enter from the blood stream (bone marrow macrophages)
Inflammation in the lungs is started by ___ macrophages
Resident. They release IL-8 and other stuff to recruit the bone-marrow macrophages.
True or False: During an inflammatory response, monocytes turn into different kinds of macrophages depending on the kind of chemotactic factors present.
____ programmed macrophages can generate inflammation that can be harmful.
Name 3 diseases that these macrophages are present in.
2. lung cancer
3. pulmonary fibrosis
What 3 things happen in resolution of defense?
1. Removal of the foreign agent
2. Reversal of the inflammatory process (e.g. the inflammatory mediators)
3. Removal of the inflammatory cells and debris
What are the 4 outcomes of resolution?
Resolution - migration, replication, and differentiation of parenchymal cells on a msotly intact matrix framework.
Destruction - irreparable tissue damage (leaving open space)
Scarring - fibroblast accumulation and deposition of collagen with permanently impaired tissue structure and function
What cell type initiated the adaptive immune response and what happens in the adaptive immune response?
Dendritic cells initiate the adaptive immune response when the sense PAMPs.
Adaptive immune response:
B and T cells
Provides antigen specificity
Upon re-exposure, immunological memory allows for a more rapid and augmented secondary immune response.
What are 3 things that can alter defense responses?
1. Cigarette smoking (increased alveolar macrophages)
2. Alcoholism (decreased mucociliary clearance, impaired epithelial cell macrophage and T cell functions)
3. Air polution