Pulmonary defense Mechanisms Flashcards
what is the purpose of the defense mechanisms in the lung
ensure efficient gas exchange and prevent infection
removal mechanisms are aimed at minimizing inflammation
what are the two locations of lung defense
Upper airway and bronchi:
- anatomic barriers
- angulation
- cough reflex
- Mucociliary apparatus
- airway epithelium
- Secretory IgA
- Dendritic cells, lymphocytes, neutrophils
Alveolar spaces:
- alveolar macrophages
- Type II alveolar cell
- Surfactants and opspnins
- Complement
- neutrophils and eosinophils
removal of particulate matter in the pharynx/oropharynx and also removal in the trachea
in the pharynx/oropharynx/nasal cavity is done by the tonsils and the adenoids
in the trachea removal by mucokinesis and coughing
What are the events of the cough reflex
- Deep inspiration
- trapping of air by shutting off its exit (glottis in the case of cough)
- initiation of expiratory effort, raising the intrathoracic pressure
- build up of pressure
- Sudden release of the trapped air at a high pressure
a cough can be triggered by chemicals, mechanical stimulation, inflammation, or be voluntary
How does the airway epithelium play a factor in the pulmonary defense
Barrier function
Defense function:
- release of bacteriostatic molecules
- regulation of the immune response-contain receptors and produce cytokines
- support the microbiome
Translocate IgA into the airway lumen
how does mucociliary clearance work
Particles larger than 2-3um and smaller than 10 um are deposited on the mucus of the upper airways
The mucus contains defense molecules of IgA, lysozyme, lactoferrin and peroxidases
Mucus blanket is dual layered
- Sol layer (aqueous)
- mucus layer
Cilia move through the sol layer striking the mucus layer above and propel it forward (mucus elevator)
this can be altered in disease states like asthma, chronic bronchitis and cystic fibrosis
what are other mechanisms of the upper airways
Intraepithelial and submucosal lymphocytes
clara cells (club cells): release surfactant to protect the lining
Dendritic cells (antigen presenting cells to naive T cells)
Cytokines (helpful in reqruitment and activation)
Large population of Tregs (modulate the immune response)
what is the first line of defense in the alveoli
Alveolar macrophages -tissue residents -long lived self renewing -Plasticity of responses: generally an M2 profile and maitenance of tolerance
Importance of the two surfactant proteins in the alveoli
Surfactant A (SP-A) and D (SP-D)
synthesized by type II and club cells
both will bind to wide range of pathogens, suppress microbial growth, damage bacterial membranes, and modulate macrophage phagocytosis, regulation of mediator production
what are some other mechanisms of defense in the alveolar space
Immunoglobulins
-IgA and IgG
Nonimmune opsonins:
-surfactant, fibronectin, MBL, and C reactive protein
Microbiome
Complement
how does the Maintenance of tolerance work in the pulmonary tissue
Anti-inflammatory environment of pulmonary tissues
-gets suupport from the microbiome
lots of IL-10 (anti inflammatory response)
-decrease in interleukins
lots of Treg
lots of TGF-B released by alveolar macrophages
what are the events that occur during pulmonary inflammation
Activation of normal immune response and subsequent tissue repair
- Cell proliferation and regeneration
- revascularization
- Tissue remodeling
Recovery
what is the acute Immune response
Activation of immune response by exogenous triggers
- TNF-a
- IL-1
Influx of inflammatory cells from capillaries into the air spaces
- TNF-a
- IL-8
Deployment of neutrophils nets
- release of leukotrienes
- oxidants
- proteases
what is the process of the recruitment of leukocytes
IL-1 and TNF-a increase expression of P and E selectins on endothelium, they bind, detach, bind, rolling of leukocyte to help slow them down, then the leukocytes can respond to the other chemokines (IL-8) to enter cell
IL-8 and ICAM/LFA1 will then bind to pull the neutrophils i (happens within hours)
VLA4/VCAM1 and CCR2/CCL2 help recruit macrophages into the area (happens within days)
What is the inflammatory Exudate and what does it cause
Causes edema: brings proteins into intimate contact with the damaged area
Proteins in the inflammatory exudate:
- Clotting proteins
- Complement (destroy bacteria)
- Kinin cascade (vasodilation to increase peremabillity of the blood vessels and stimulate pain receptors)
- Fibrinolytic protein (degrades the clot when the wound has healed)
Chronic inflammatory response
Over time:
- infiltration of activated T cells and M1 macrophages
- mucus hypersecretion
- substantial remodeling of tissue leading to fibrosis
Early phase acute atopic response to type I hypersensitivities
Minutes:
-Cross linking of mIgE
-degranulation of mast cells
-Sneezing, pruritis, rhinorrhea, congestion
-Performed mast cell cytokines and inflammatory proteins recruit inflammatory cells to the area
(IL-4 for type 2 helpers, IL-5 for eosinophils, histamine and leukotrienes leading to bronchial constriction)
Type 1 hypersensitivities: Late Phase chronic atopic response
hours 4-12:
- influx and activation or eosinophils, neutrophils, basophils and lymphocytes (Th2)
- 10 fold increase in mast cells present in area and increased expression of Fc3 receptors
- systemic symptoms: fatigue, myalgias, asthma
Esoinophils:
- proinflammatory mediators
- local tissue damage, sinus infections
- chronic hyperplastic eosinophilic sinusitis (CHES)
Chronic asthma related airway remodeling
Leukotrienes C4, D4, and E4
-induce bronchospasm, vascular permeability, and mucus production
Prostagladins D2, D2, F2
-Induce bronchospasm and vasodilation
recruitment of smooth muscle cells and fibroblast leading to deposition of collagen in the submucosa
Treatments: Anaphylaxis
epinephrine
causes vascular smooth muscle cell contraction leading to increase cardiac output and inhibits bronchial smooth muscle cell contraction
Treatments: Bronchial asthma
Corticosteroids
-reduce inflammation
leukotriene antagonists
-relax bronchial smooth muscle and reduce inflammation
Phosphodiesterase inhibitors
-relax bronchial smooth muscle
Treatments:Various allergic diseases
Desensitization (repeated administration of low doses of allergens)
-unknown may inhibit IgE production and increase production of other Ig isotypes; may induce T cell tolerance
Anti-IgE antibody
-neutralizes and eliminates IgE
Antihistamines
-Block actions of histamine on vessels and smooth muscles
Cromolyn
-Inhibits mast cell degranulation
TH17 mediated inflammation in COPD
Th17 cytokines induce IL-8 and G/GM-CSF secretion from airway epithelial cells
-IL-17, IL-22
Recruitment of large population of and inflammatory macrophages and neutrophils
- leads to chronic inflammation in range of airway diseases
- CD8+ cell
- TH17
- Small airway narrowing and alveolar destruction
decrease in Treg
-lead to immuno-suppression
Ventilator Associated Lung Injury
Iatrogenic
Physical damage
-over inflation
-mechanical stress
Biodamage
- HYper-oxygenation
- free radical production
- influx of neutrophils into tissue from activation of endothelium
Neutrophil netosis leading to platelet activation and clot formation
