Physiology, Pulmonary Stress Response
The lungs are one of the few organ systems that are most challenged by stress due to its direct contact with the outside world. They play a significant role in preventing the development of disease with their well-equipped defense system, warding off toxic insults, such as smoke, exhaust, and microbes.
Depending on the location within the lung, there are several anatomical defenses present to ward off harmful particles, such as dust, viruses, bacteria, fungi, soot, among others. The size of each particle determines how the lungs defend themselves.
Along with these anatomical barriers, the integrated stress response (ISR) becomes activated by one or more of these toxic triggers and thereby activates one of four stress-sensing kinases. The balance of these cytoprotective and damaging factors induced by the kinases leads to the negative effects on the lungs due to the environment.
Issues of Concern
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The purpose of the pulmonary system is to bring oxygen in for use in bodily functions. At the same time, it introduces the body to several foreign particles. Although the ideal goal would be to ward off negative stressors, such as smoke, pollution, and microbes, to name a few, the reality is far from ideal. It is near impossible to escape the stressors that cause damage to the lungs. Humans are constantly surrounded by exhaust, pollution, smoke, and many different pathogens. Therefore, with exposure to a combination of these pathogens throughout life, a person may develop disease even with these protective mechanisms.
Cilia are tiny hair-like projections lining the airway to protect the lungs from toxins. They are also covered by a thin layer of mucus to help move the trapped particles towards expulsion via the cough reflex. Cilia are located in the upper airways whereas alveolar macrophages are in the lower airways, taking care of particles that are smaller in size that may have been missed by the cilia and/or mucus. Alveolar macrophages are white blood cells that ingest and digest smaller particles, less than 2 micrometers. When a large number of particles enter the lung, more alveolar macrophages can be recruited, including neutrophils if a bacterial infection were the concern.
On a smaller scale, the integrated stress response (ISR) becomes activated by one or more of these toxic triggers and thereby kicks off one of four stress-sensing kinases: heme-regulated inhibitor (HRI), protein kinase R (PKR), PKR-like endoplasmic reticulum kinase (PERK), and general control nonderepressible 2 (GCN2). A toxic insult activates each kinase: iron deficiency and oxidative stress activate HRI, dsDNA in viruses and bacteria activates PKR, hypoxia and misfolded proteins activate PERK, and amino acid starvation and UV light activate GCN2.
These stress-sensing kinases furthermore phosphorylate eukaryotic translation initiation factor (eIF2a) and reduce global protein synthesis as a protective mechanism. It wards off stressing the endoplasmic reticulum (ER) from an overproduction of proteins, it reduces the consumption of iron and amino acids in times of starvation of these proteins, and it blocks viral or bacterial replication by hindering protein synthesis.
The eIF2a also promotes the translation of activating transcription factor 4 (ATF4), which thereby has several functions. Activation of ATF4 allows for cellular adaptation to stress via increased production of transporters, such as for amino acids to overcome nutrient limitations. ATF4 also induces CCAT enhancer-binding protein homologous protein (CHOP), a transcription factor that aids the eIF2a phosphatase, GADD34 (growth arrest and DNA-damage 34), allowing for the synthesis of various proteins. This protein synthesis can further induce damage to the ERs in the lungs if the insult continues chronically by overpopulating the ERs. CHOP also induces ER oxidase 1a to promote oxidative protein folding, the production of ROS species, as well as IL-8 induction, a proinflammatory gene all leading to chronic lung damage.
There are five phases or periods of lung development: embryonic, pseudoglandular, canalicular, saccular, and alveolar. The development of the lungs begins at week 4 of pregnancy which is the embryonic period. This stage spans from weeks 4 through 9 and coincides with the pseudoglandular period which spans from weeks 5 through 18. At this time there is the formation of the major airways. The canalicular period spans from weeks 16 through 27 and includes epithelial differentiation and air-blood barrier formation. From weeks 26 through 38, is the saccular period, where surfactant production begins, depicting viability. This period also allows the expansion of spaces within the lungs. Lastly, the alveolar period concludes lung maturity by forming secondary septations and continuing to produce surfactant. The presence of sufficient surfactant is the indicator for lung maturity.
The pulmonary system is the organ system solely involved in this inflammatory stress response to external pathogens and toxins.
The purpose of the lungs is to inhale oxygen (O2) and exhale carbon dioxide (CO2). Room air (21% oxygen) enters the lungs through negative pressure due to the pulling pressure of the diaphragm, distributes throughout the alveoli, and ventilates the capillaries at the alveolar-capillary membrane, participating in gas exchange for CO2. The CO2 then travels back through the alveoli and upper airways to be exhaled into the environment. This mechanism provides the ability for the body to maintain oxygenation as well as an acid-base balance. While participating in this respiration, pathogens can enter and exit at their own will. The mucociliary escalator and alveolar macrophages are the first to ward off such insults.
As discussed, the particles that exist in our environment are endless. Therefore, our lungs have anatomical defense mechanisms to avoid these toxins. The mucociliary escalator begins from the level of primary bronchi to the level of the terminal bronchioles. It consists of cilia and goblet cells that secrete mucus. Larger particles are warded off in these areas, triggering the cough reflex to allow the exit of pathogens that may have entered the bronchi. Further down extending from the terminal bronchioles to the alveoli, the alveolar macrophages engulf smaller particles (less than 2 micrometers). They break the particles down and digest, recruiting more macrophages or other cells, such as neutrophils, to help ward off the stressors.
Pulmonary function tests are one of the first steps to help establish a diagnosis of obstructive versus restrictive lung disease in the diagnosis of any chronic lung pathology. Chest X-rays also help determine the acute or chronic pathology of the lung, whether it shows a ground-glass appearance, seen in interstitial lung disease, hyperinflation, such as seen in COPD, or consolidation, suggesting pneumonia. Further testing, such as CT scans, can also be helpful to get a better look at pathology initially seen on the X-ray or denoted with the clinical symptomology.
The stress in the lungs is mainly the result of external pathogens and toxins, such as those from smoke, pollution, bacteria, and viruses, among others. As mentioned above, the chronic exposure to such toxins allows for the bypass of the airways' defense. The particles are both too small to cough out via the mucociliary escalator or to engulf via alveolar macrophages and they rather induce the ISR. The kinases involved in the ISR cause damage to the lung as a means of protection and thereby cause chronic disease, such as COPD.
Several chronic lung diseases such as COPD, cancer, bronchopulmonary dysplasia, pulmonary fibrosis, cystic fibrosis, and alpha-1 antitrypsin deficiency, severely affect the lungs via the cellular stress response. Smoke inhalation injures the cilia involved in the mucociliary escalator, allowing more and more particles into the lungs, activating the ISR.
Research has shown that heightened ER stress, a CHOP-dependent mechanism that leads to oxidative protein folding, has been seen in increased exposure to cigarette smoke in vitro, which thereby likely contributes to the COPD diagnosis. Higher levels of ER stress are also present in chronic smoker’s lungs, such as those with COPD. Although CHOP helps contribute to the higher ER stress levels, it also holds a protective mechanism, which is mostly unknown but has correlations with decreased epithelial permeability in the lungs.
Infections of the lungs resulting from several microorganisms that trigger the ISR. As mentioned above, PKR is triggered by dsRNA in viruses that inhibits protein translation and thereby stops the replication of the virus.
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