BASIC CONSIDERATIONS

16.2 Chandrahas T Deshmukh, Mukesh Agrawal

Respiratory tract may be divided into two broad seg­ments: (a) Upper respiratory tract extending from nose to oropharynx and including related structures, e.g.

Anatomically, lungs are paired structures, located on both sides of mediastinum in thoracic cavity and covered with two layers of pleura. Each lungs is divided into lobes by pleural invaginations and septa (3 on Rt side/2 on Lt side) and further into bronchopulmonary segments (10 on Rt side/8 or 9 on Lt side), ach with independent bronchial and blood supply (Fig. 16.1). These lobes and broncho-pulmonary segments restrict direct progression of disease.

Histologically, lung is a spongy tissue with three important components: (a) airway structures, i.e. distal bronchial tree, (b) alveoli-the air-blood interface area, each supplied by own respiratory bronchiole, and (c) interstitial spaces with network of capillaries.

Airways are lined by ciliated epithelial membrane that gradually changes from pseudo-stratified columnar epithelium in upper airways to cuboidal epithelium in terminal respiratory bronchioles. Smooth muscle content of airways also declines distally. Presence of cilia, mucus­secreting goblet cells and immunological cells in lamina propria are important defence barriers in airways.

Lung surfactant is a heterogeneous mixture of phospholipids and proteins, secreted into alveoli from 24^th week onwards, by specialized alveolar cells - type II pneumocytes. Lining the alveoli, surfactant prevents end-expiratory alveolar collapse and facilitates their re-expansion by reducing the surface tension (Ch 12.13). Embryologically, respiratory system develops from two different sources:

Fig.

a. Airways develop as a ventral out-pouch or diverticula from the endodermal epithelium of the primitive foregut, which divides to form two main-stem bronchial buds and burrow into surrounding mesenchyme that separates foregut from the coelomic cavity. These buds branch further to develop into complex bronchial tree and alveoli, passing through various

Fig. 16.2: Development of respiratory system: (A) Early embryonic period; (B) Late embryonic period; (C) Early embryonic period; (D) Late embryonic period; (E) Pseudoglandular stage; (F) Canalicular stage; (G) Saccular stage; (H) Alveolar stage.

stages of development, i.e. (a) embryonic period, (b) pseudoglandular period, (c) canalicular period and (d) alveolar period (Fig. 16.2). Lining cells of these buds differentiate into ciliated, secretary, globular or neuroendocrinal cells, each with specialized function.

b. Pulmonary vasculature and supporting structures, e.g. pleura, alveolar septa, interstitium, smooth muscles and cartilaginous part of airways, develop from mesenchymal tissue. Soon after their appearance, bronchial buds are surrounded by a vascular plexus from systemic circulation that gradually connects with pulmonary artery/veins to complete pulmonary circulation by 7^th week of life. However, some connection from systemic circulation is retained via bronchial vessels throughout the life, which may be life-saving as collaterals in cases of severe pulmonary vascular obstruction, e.g. heart diseases with pulmonary stenosis.

About 50 million alveoli are present at birth. In first 2 years of postnatal life, alveoli continue to grow in numbers and volume, though vascular growth is disproportionately more than alveolar growth. After 2 years, most of alveolar growth is in terms of volume rather than in numbers.

Fetal lung development depends on many factors, the most important being:

• Specific gene families, i.e.

• Fetal lung secretion, essential for development of acini, and

• Hormones, e.g. steroids and thyroid hormones, which regulate surfactant production.

Respiratory Defense Mechanisms

Lungs are constantly exposed to external environment containing pathogens, allergens and other pollutants. Important defence mechanisms to protect the lungs and respiratory tract from this onslaught are shown in Table 16.1.

These defense mechanisms may be impaired by—(a) Environmental insults, e.g. smoking and air pollution,

TABLE 16.1: Respiratory defense mechanisms

• Mechanical

- Nasal filtering, warming, humidification of air

- Cough reflex

- Mucociliary clearance in airways*

- Collateral alveolar ventilation**

• Immunological

- Phagocytosis by alveolar/interstitial macrophages

- Secretary IgA to inactivate pathogens and toxins

- IgM/IgG mediated immune response

- IgE mediated allergic/inflammatory response

- Others: Opsonins, lysozymes, interferon, etc. *upward movement of mucus at the rate of 10 mm/minutes **via pores of Kohn and canals of Lamberts

exposure to cold, (b) Pathological insults, e.g. starvation, hypoxia, acidosis and viral infections, (c) Hypersensitivity reactions, e.g. asthma or allergic rhinitis, (d) Drugs, e.g. steroids, anesthetics and narcotics, and (e) Vascular disturbances, e.g. pulmonary edema/embolism.

Physiology of Respiration

In utero, gaseous exchange depends exclusively on placenta. Act of breathing is absent and fetal lungs are-

(a) filled with a specific fluid, actively secreted by alveoli and mixed with amniotic fluid, (b) receive lt;2% of total cardiac output.

An electrolyte-rich fluid is constantly produced and filled in fetal alveoli, essential for their development. However, presence of this fluid is incompatible with postnatal alveolar breathing and its secretion declines in late gestation.

At birth, gaseous exchange system switches-over from placental to pulmonary dependence, with following major adaptive mechanisms:

• Initiation of central respiratory drive, due to mecha­nical stimulation of baby and sudden hypoxia after severance of placental circulation,

• Switch-over from parallel to sequential pulmonary and systemic circulation,

• Absorption of fetal lung fluids to create an air-blood interface in alveoli, separated from highly porous and permissible alveolar epithelium,

• Increased production and spread of surfactant over inner alveolar lining, to prevent end-expiratory collapse and facilitate re-expansion.

Postnatal respiration: Primary aim of respiration is to provide adequate gaseous exchange, which requires-(a) adequate ventilation of alveoli, (b) adequate perfusion of interstitial capillary network, and (c) adequate diffusion of gases across the alveolar membranes. Some important aspects of these mechanisms are as follows:

A. Ventilation (breathing) physiology is complex and still evolving, though four components play a major role in regulation of normal breathing:

a. Afferent feedback from—(a) stretch/temperature­sensitive receptors, located in larynx and upper airways (via superior laryngeal nerve); (b) chemoreceptors located in carotid or aortic bodies, sensitive to arterial O₂ and CO₂ tensions (via carotid/aortic sinus nerves); (c) skin, mucosal or hypothalamic receptors, sensitive to thermal or metabolic changes.

b. Central controller located in medulla, tentatively identified and named as nucleus tractus solitarius, nucleus ambiguous/retroambiguus and pre-botzinger nucleus. However, these centers act as the controller of breathing and not the generator of normal rhythm, which is yet unidentified. Note that respiratory con­trol mechanism operates on negative feedback and not the positive feedback, i.e. central controllers merely attempt to rectify any deviation from normal breathing.

c. Efferents are conveyed via phrenic nerve to diaphragm and other muscles of respiration.

d. Effectors (respiratory muscles): Diaphragm and intercostals are most important muscles in breathing, though the relative contribution varies with age. Breathing during early infancy is mainly intercostals- dependent (thoraco-abdominal) that gradually switches-over to mature diaphragm-dependent breathing (abdomino-thoracic) by the end of infancy. Other muscles, e.g. nasal, orophraryngeal and neck muscles also support the breathing efforts, though their contribution is minor (accessory muscles), except during high demand, i.e. hypoxia and respiratory distress.

B. Pulmonary perfusion: After initial hemodynamic changes at birth (Ch 17.1.3), pulmonary circulation offers much lower resistance to blood flow than systemic circulation. However, pulmonary resistance depends on two important factors—(a) intrathoracic pressure, (b) alveolar/blood gases.

Intrathoracic pressure affects the pulmonary resistance by mechanical means. During inspiration, alveolar vessels compress while extra-alveolar vessels dilate, leading to net changes in pulmonary resistance. As the effect of lung inflation predominates over extra-alveolar vessels at low lung volume and alveolar vessels at high lung volume, pulmonary resistance decreases at lower lung volumes and increases at higher lung volumes - a phenomena with considerable significance during mechanical ventilation.

Pulmonary arterioles are highly sensitive to alveo­lar hypoxia and hypercarbia-responding with vaso­constriction that allows re-shunting of non-oxygenated blood away from poorly ventilated areas. However, severe or persistent hypoxia/hypercarbia may lead to severe pulmonary hypertension and cardiac failure. Prolonged changes in pulmonary resistance due to

chronic hypoxemia or overdistended alveoli can produce smooth muscle hypertrophy with progressive vascular obstruction, leading to development of pulmonary arterial hypertension and cor pulmonale in chronic lung diseases.

Pulmonary circulation is also the site of active exchange of water and solutes between vascular space and lung interstitium via endothelial cells or inter- endothelial cell junctions. This exchange is regulated by relative hydrostatic and osmotic gradients as well as vascular permeability. Abnormalities of this exchange are responsible for pulmonary edema, seen in many conditions, e.g. left heart failure, pulmonary venous hypertension and acute respiratory distress syndrome (ARDS).

C. Pulmonary diffusion: Gaseous diffusion across the alveolar epithelium depends on many factors—(a) fractional oxygen concentration in inspired air or FiO₂,

(b) partial pressure of O₂/CO₂ in venous blood, (c) Oxygen carrying capacity of hemoglobin, and most importantly, (d) alveolar ventilation and perfusion.

Relative ventilation and perfusion in different parts of lung is a critical determinant of net pulmonary diffusion and tissue oxygenation. All parts of lungs are not equally ventilated or perfused. Normally, the upper parts of lungs are better ventilated and lower parts are better perfused. In disease, ventilation and perfusion in different parts of lung may be affected proportionately or disproportionately, leading to altered ventilation­perfusion ratio and consequent hypoxia/hypercarbia.

Since air-blood barrier in the lungs has lower diffusion conductance for O₂ than for CO₂, arterial pO₂ is closer to alveolar pO₂ than alveolar: arteriolar pCO₂ relationship. Normal alveolar: arteriolar pO₂ difference is 5-6 mm Hg, due to normal channels of pulmonary-bronchial shunting. Higher alveolar-arterial oxygen difference indicates adverse changes in ventilation-perfusion ratio, seen in many respiratory disorders.

16.3