What are the two divisions of lung defense?
upper airways and bronchi
What are the defense mechanisms of the upper airway and bronchi?
dendritic cells, lymphocytes, neutrophils
What are the defense mechanisms of the alveolar spaces?
type II alveolar cell
surfactants and opsonins
neutrophils and eosinophils
What is the sequence of events for the cough reflex?
- deep inspiration
- trapping of air by shutting off its exit (glottis)
- initiation of expiratory effort, raising intrathoracic pressure
- build up of pressure
- sudden release of trapped air at a high pressure
*TRIGGERED* by checmicals, mechanical stim, inflammation, or voluntary action
What are the defense functions of the airway epithelium?
release bacteriostatic molecules
regulate immune response with receptors/cytokines
Epithelium also works as a barrier and can translocate IgA
Describe mucociliary clearance
particles between 2-10um are deposited on the mucous membranes of the upper airway
mucous contains IgA, lysozyme, lactoferrin and peroxidases
the mucous membrane is two layers: sol (aq) and mucous
the cilia move through the sol layer striking the mucous layer above and propel the particles forward, geting them stuck in the mucous
* this process is altered in asthma, chronic bronchitits, and CF *
What are some other immunological defenses in the airways?
lymphoctes (submucosal and intraepithelial)
Club cells (clara)
lots of Tregs
what cell type is the first line of defense in the alveoli?
reside in tissue
long lived, self renewing
plastic responses-usually M2, help maintain tolerance
What is the role of surfactant?
made by type II pneumocytes and Club cells, there is SP A and SP D that both bind and supress pathogens and microbial growth, damage bacterial mebranes, and modulate macrophage phagocytosis
What immunoglobulins are present in the alveolar space?
What non-immune opsonins are present in the alveolar space?
IgA and IgG
surfactant, fibronectin, MBL, CRP
How is tolerance maintained in the airway?
anti-inflammatory environment of the pulmonary tissues as well as support from the microbiome
After inflammation of the pulmonary tissue, how is the tissue recovered?
activation of normal immune response and subsequent tissue repair by
- cell proliferation and regeneration
- tissue remodeling
What are the main events of an acute immune response in the lungs?
activation of immune responses by exogenous triggers
influx of inflammatory cells from capillaries into air spaces
deployment of neutrophil nets
recruitement of leukocytes
formation of exudate
How are leukocytes recruited to the site of infection?
IL1 and TNF increase expression of P and E selectins on endothelium within the first 2 hours
these “roll” on the endothelium by binding and releasing continuously until the leukocytes slow down
once they slow down, they respond to chemokines in the area produced by TNF and IL1
chemokines increase affinity and clustering of integrins for ligand binding
leukocytes attach, flatten and squeeze through endothelium into tissue
What chemokine/cytokines are involved in neutrophil recruitment in the first few hours?
What chemokine/cytokines are involved in macrophage recruitment in the first few days?
Formation of inflammatory exudate starts with
edema which brings plasma proteins into intimate contact with the damaged area
proteins in the inflammatory exudate include
- clotting proteins: prevents further blood loss
- complement: destroys bacteria
- kinin: vasodilate, stimulates pain
- fibrinolytic protein: degrades clot after healing
Over time, a chronic inflammatory response can be triggered by the following:
infiltration of activated T cells and M1 macrophages
substantial remodeling of tissues leading to fibrosis
instead of the normal tissue recovery that was in a previous FC, during chronic inflammation, what happens?
dysregulation of the inflammatory cascade leading to tissue injury and disease
Within minutes, what occurs in a type I hypersensitivty reaction?
cross linking of mIgE
degranulation of mast cells
sneezing, pruritis, rhinorrhea/congestion
preformed mast cell cytokines and inflammatory proteins recruit inflammatory cells to the area
Within 4-12 hours, what occurs in the type I hypersensitivity respinse?
influx and activation of eosinophils, neutrophils, basophils and Th2 lymphocytes
10x increase in mast cells with increased Fce receptors
systemic sx of fatigue, myalgias, asthma
What are eosinophils?
leading to local tissue damage, sinus infections
can cause chronic hyperplastic eosinophilic sinusitis
How does airway remodeling occur in chronic asthma?
Leukotrienes C4, D4 and E4 induce bronchospams, vascular permeability and mucus production
Prostaglandins D2, E2, F2 induce bronchospasm and vasodilation
recruitment of Smooth Muscle cells and fibroblast lead to deposition of collagen in submucosa (leading to remodeling)
treatment and MOA for anaphylaxis
causes vascular smooth muscle cell contraction, increasing cardiac output to counter shock and inhibits bronchial smooth muscle cell contraciton
What is the treatment and MOA for bronchial asthma?
corticosteroids, reduce inflammation
leukotriene antagonists: relax bronchial smooth muscle and reduce inflammation
phosphodiesterase inhibitors: relax bronchial smooth muscles
What are the treatmetns and MOAs for various allergic diseases?
desensitization: may inhibit IgE production, or induce T cell tolerance
Anti-IgE ab: neutralizes and eliminates IgE
Antihistamines: block actions of histamines on vessels and SM. M.
Cromolyn: inhibits mast cell degranulation
What is Th17 mediated inflammation in COPD?
Th17 cytokines induce IL8 and G/GM-CSF secretion from airway epithelial cells (IL 17 and 22)
this causes recruitment of large population of inflammatory macrophages and neutrophils
this causes small airway narrowing and alveolar destruction that is irreversible
What is ventilatory associated lung disease?
causes physical damage and biodamage
Physical: over inflation and mechanical stress
Biodamage: hyperoxygenation, free radicals, increase in neutrophils into tissues from endothelial activation, increased netosis leading to platelet activation and clotting
Vaping associated lung injury
presents with ARDS
bilateral infiltrates on CXR
absence of infection
Vaping use within last 90 days
no other plausible cause
26 deaths and 1300 cases at end of 2019
PNA caused by inhalation/aspiration of lipids
seen in increase due to vaping CBD/THC or vit. E acetate as well as from essential oils: vicks, castor oil, olive oil, mineral oil, petro jelly, lip gloss
tx: supportive, steroids, antimicrobials secondary to complication.