# Structural Biochemistry/Cell Signaling Pathways/Respiratory System/Chronic Obstructive Pulmonary Disease
## Overview

Chronic obstructive pulmonary disease (COPD), otherwise known as pulmonary emphysema and chronic bronchitis, is triggered by the exposure of the airways to potentially harmful gases or particles. The inhalation of these injurious gases consequently lead to the constant inflamed state of the airways themselves which are ultimately highlighted by clear obstruction of airflow and hyperinflation--unwanted expansion of the lung. On a purely mechanical scale, the effects of COPD on the respiratory system can be revealed through the understanding of pressure-volume (P-V) relationships.

## Airway Blockage

Airway blockages are categorized into three groups: (1) tissue abnormality around the airways, (2) airway wall thickening, (3) partial obstruction of lumina; in this case, the bronchi located in the lungs. The first group mentioned involves airway constriction due to the rapid loss of radial traction while the second group is caused by muscle hypertrophy or edema. Finally, the third group is a direct result of an accumulation of mucous that lead to the formation of semisolid plugs around the airways. Both emphysema and chronic bronchitis are associated with COPD and are therefore characterized by the three groups mentioned above.

## Pathology of COPD

In patients with COPD, there are clear pathological changes not only in small airways, but in larger ones as well. These changes are usually located around the pulmonary and parenchyma vasculature regions and are exemplary of continuous damage and repair of the airways themselves. The consequential inflammatory response triggered may be an internally genetic factor, or may be attributed to the harmful effects of cigarette smoke. Although the existence of cigarette smoke is an alarming indicator in the manifestation of COPD, there have been confirmed instances where patients develop COPD without cigarette smoke exposure, which ultimately leads to the fundamental cause of this respiratory disease. As oxidative stress and imbalance grows between proteases and antiproteases, the inflammatory response of the disease is greatly amplified. Both these proteases serve to protect the connective tissue in the system from deteriorating and tension between them triggers the inflammatory state. More specifically, the inflammatory response is enhanced by the CD8+ cytotoxic Tc1 lymphocytes and inflammatory mediators--inflammatory cells. An explanation for these occurrences is embedded in the oxidative DNA damage of lung epithelial barrier cells (LEBCs). In detail, the damaging inhaled gases induce damage upon the DNA of the LEBCs and these mutations are highlighted at the microsatellite DNA level of the LEBCs themselves. The newly mutated LEBCs then relay information to the lymph nodes by way of dendritic cell (DC) recognition. Once the T lymphocytes receive this information , a CD8+ cytotoxic T-lymphocyte massive production results. Finally, these CD8+ T lymphocytes will release granzymes and perforin which will attract the mutated LEBCs, resulting in cellular destruction.

## COPD Pathophysiological Characteristics

As mentioned, COPD is characterized by two symptoms: Hyperinflation and Airflow Obstruction.
Hyperinflation is usually described by the loss of the elastic recoil present within parts of the respiratory system. This symptom is seen regularly in COPD patients stricken with emphysema and the body consequently tries to keep the airways open and the air trapped during premature closure. Hyperinflation undoubtedly has unwanted effects on not only the main respiratory system consisting of the lungs, but also the diaphragm. It tends to affect the function of the diaphragm to regulate breaths by increasing the work of breathing. Hyperinflation affects the diaphragm in two ways. First, the diaphragm is flattened which will lead to a decrease of the apposition zone between the abdominal wall and the diaphragm itself. Second, the muscle fibers of the diaphragm become shorter and are therefore unable to generate enough inspiratory pressures that will override trans-pulmonary pressures. Given these two effects, there will be an increase in the proportion of the type I fibers (fatigue resistant and slow twitch) and an increase in mitochondrial concentration and the efficiency of the electron transport chain (ETC). This occurrence will then lead to further impaired respiratory muscle function as the diaphragm becomes weaker.
Airflow during exhalation is defined as the balance between the airway resistance that limits flow and the elastic recoil of the lungs the promote flow. Hence, the factors that result in the blockages in the lumen along with the increased resistance are the presence of secretions, the hypertrophy of submucosal glands, and the increased tone of bronchial smooth muscle. It is the great difference resulting between the intraluminal pressure and the surrounding pressure that ultimately causes the airflow obstruction. For example, in emphysema, there is an obvious loss of elastic recoil on the walls of small airways due to the reduced numbers of elastic tissue in the pulmonary parenchyma. In addition, the lack of cartilage along the wall of these airways leads to even less elastic recoil.

## Lung Compliance

The respiratory system relies on its elasticity to facilitate the function of the respiratory muscles; thereafter, these muscles will supply the respiratory system with the pressure gradient (difference) required to move air into the airways. It is through the use of the pressure-volume (P-V) relationships that the static mechanical properties of the respiratory system are mapped. The curves represented by the (P-V) relationships are acquired as volume is changed in increments from residual volume (RV) to total lung capacity (TLC) to form loops. More specifically, these loops are facilitated by the elastic properties of the chest wall and the lungs including the unit changes in lung inflation and deflation. The nonlinear trendline represented by the P-V curve demonstrates that as lung volume increases, the elastic portions approach distensibility limits.

## COPD and the interrelationship between resting and dynamic hyperinflation

In COPD patients, there exists a disease-induced increase in the end-expiratory lung volume, abbreviated as EELV. This is a direct result of the encroachment of the exercise tidal volume (VT) on the upper alinear extreme of the respiratory system's given P-V curve as shown by the figure. It is at this extreme that elastic loading on the system is clearly perceived in an increasing fashion. COPD patients face challenges in their inability to further expand their VT, thus resulting in an inability to increase their inspiratory reserve volume or IRV. In these instances, those with COPD will have recoil pressure directed inwardly not only during their resting phases but also during periods of exercise, causing an extra inspiratory load on respiratory muscles, which is clearly unfavorable.
* P-V relationship of the total respiratory system. (a) shows a normal distribution (b) shows COPD distributionP-V relationship of the total respiratory system. (a) shows a normal distribution (b) shows COPD distribution
To recap, patients with COPD, the ability to expand VT is reduced; thus, the inspiratory reserve volume (IRV) is reduced as well. Thus, the recoil pressure of both the lungs and the chest wall in patients experiencing hyperinflation is inwardly directed not only during rest, but also during exercise. As a result, intrapulmonary pressures do not stabilize at the zero value any longer, which shows that the auto-PEEP (positive end-expiratory pressure) must be overridden to instill inspiratory flow.
The static compliance (C) of the lung is defined as the change in lung volume per unit change in the pressure difference between the interior of the alveoli and the surface of the lungs.
    $C={\frac {\Delta V_{L}}{\Delta (P_{A}-P_{Pl})}}$
In this figure, C is the compliance, ΔV$_L$ is the change in lung volume, and Δ(P$_A$ -P$_{Pl}$) is the change in the transpulmonary pressure. According to the formula above, the pressure in the trachea minus the intrapleural pressure is equal to the transpulmonary pressure. Thus, this transpulmonary pressure value is representative of the total pressure difference across the lung. Despite this observation, it must be noted that the internal alveoli pressure is equal to the airway pressure at the start or finish of every breath taken. When defined strictly by terms, the end-inspiratory and end-expiratory alveolar pressure is 0 cm H2O. In the P-V curve shown, one can clearly see this phenomenon when the horizontal distance from the starting or stabilized point "0" demonstrates the pressure due to elastic forces on the whole respiratory system. In certain systems, this elastic pressure attains a negative value below the FRC and retains a positive value when shown above the FRC level. With these certain properties, one can clearly deduce that the pressure differences between the atmospheric pressure and the pressure at the mouth shows the necessary pressure to lengthen/expand the respiratory system when in the process of the respiratory cycle. With regards to the figure itself, one can clearly observe indications of looping in the P-V curve. When specified, this loop represents the effects of increased lung volume. When lung volume increases, the specific elastic characteristics associated with the system readily reach distensibility limits. Given this effect, there will be a new change in transpulmonary pressure--incrementally small increases in lung volume. As such is the case, lung compliance is at the greatest when the residual volume (RV) is attained, while the lowest value for lung compliance is reached at the higher extremes of lung volumes.

## Trends Caused by High Compliance

With an increased lung compliance, hyperinflation and tidal breathing factors are also taken into account. In this case, reduced volume changes are a direct result of the hyperinflation and tidal breathing's ability to force the respiratory system to focus only on the flatter part of the compliance curve, an area where progressive pressure increases. In terms of direct measurement, there is a clear distinction in the measurement of lung compliance during stationary and moving events. When lungs are on their stationary period, compliance is measured using a static method. However, dynamic compliance is also used when the measurements of lung volume are conducted at the finish of inspiration and expiration when the lungs reach a pseudo-stationary state that resembles that observed during ordinary/immobile lung expansion. When both the static and dynamic compliance methods are used on patients without COPD, control variables, similar results are obtained in both tests. However, discrepancies between the two exist in patient with the disease. For example, those with emphysema show deviations in their lung capacity for static lung compliance.

## COPD Summary

Given the variety of pathological aspects of COPD, the dynamic and static representations of the lung in COPD vary as well. As mentioned several times, the loss of elastic recoil in the bronchi of the lungs will result in an abnormal pressure difference between the inside of the alveoli and the lung surface. This difference in pressure was defined as transpulmonary pressure. Thus, patients with emphysema have high compliance in their lungs which expands largely in comparison to a normal lung with low compliance, an event known as hyperinflation.

## References

* ↑ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3486437/
* ↑ West JB. Pulmonary Pathophyiology: The Essentials. 6th edition. Vol. 52. Baltimore, MD, USA: Lippincott Williams and Wilkins; 2007.
* ↑ Tzortzaki EG, Siafakas NM. A hypothesis for the initiation of COPD. European Respiratory Journal. 2009;34(2):310–315. [PubMed]
* ↑ Fishman AP, Elias J, Fishman JA, et al. Fishman’s Pulmonary Diseases and Disorders. 4th edition. Vol. 1. New York, NY, USA: Mc Graw Hill; 1997.
* ↑ O’Donnell DE, Webb KA. Exercise. In: Calverley PMA, MacNee W, Pride NB, Rennard SI, editors. Chronic Obstructive Pulmonary Disease. 2nd edition. London, UK: Arnold; 2003. pp. 243–269.
* ↑ O’ Donnell DE, Parker CM. COPD exacerbations · 3: pathophysiology. Thorax. 2006;61(4):354–361. [PMC free article] [PubMed]
* ↑ Levitzky MG. Pulmonary Physiology. 7th edition. New York, NY, USA: The McGraw-Hill Companies; 2000.
* ↑ Cotes JE, Chinn DJ, Miller MR. Lung Function. 6th edition. Blackwell Publishing;