Respiratory System Objectives

- Describe the components and functions of the conducting and respiratory portions of the respiratory system. - Describe the embryologic steps in the development of the respiratory system. - Describe and compare the characteristic microscopic features and functions of the different regions and airways of the respiratory system, including lining epithelium, glands, cartilage, smooth muscle and elastic fibers. Respiratory System

* Introduction * Conducting portion * Respiratory portion * Pleura Respiratory System

• Introduction – Anatomy of the respiratory system Two Functional Parts of the Respiratory Tract

* Conducting portion - Conduct air to and from alveoli - Condition the air (warm, humidify, filter) * Respiratory portion - Gas exchange Trachea Primary bronchus

Secondary bronchi

Right lung Left lung Conducting portion Bronchiole (1 mm or less in diameter)

Terminal bronchiole

Respiratory bronchiole

Alveolar duct Respiratory portion

Alveolar sac Respiratory System

* Embryology Pharyn x Esophagus

Lungs Stomach

Liver

Pancreas Duodenum (½)

Gallbladder

Stuff that develops from the foregut Endoderm gives rise to the epithelium and glands of the larynx, trachea, bronchi and the pulmonary epithelium. Mesoderm gives rise to the connective tissue, cartilage and smooth muscle of the respiratory tract.

Development of respiratory diverticulum (bud) Development of bronchi and bronchioles

- The lung bud divides into two bronchial buds, which divide and form secondary and tertiary bronchi. - As bronchi develop, the surrounding mesenchyme forms cartilage, smooth muscle, connective tissue and capillaries. When can the baby breathe?

- By week 24, respiratory bronchioles are present and lungs are vascularized. Respiration is possible – but chances of survival outside placenta are slim. - Weeks 24-26: terminal alveolar sacs develop and type II pneumocytes secrete surfactant (decreases surface tension) - By week 26-28: there are enough alveolar sacs and surfactant to allow a prematurely born infant to survive without medical intervention. - 95% of mature alveoli develop after birth!

- The newborn infant has only 1/6 – 1/8 the number of alveoli as adults.

- Most alveolar growth is done by age 8. Lungs at Birth

- At birth, the lungs are half-filled with amniotic fluid. - This fluid is cleared through the mouth and nose by pressure on thorax during delivery. - It also is reabsorbed into pulmonary blood vessels and lymphatics. Respiratory System

* Introduction

* Conducting portion - - Larynx - Trachea - Bronchi - Bronchioles Walls of the Conducting System

* The walls of the conducting system change in thickness and composition from region to region.

* Components include: - Epithelium (“respiratory epithelium”) - Lamina propria - Mucous and serous glands - Cartilage - Smooth muscle - Adventitia Respiratory System

* Introduction

* Conducting portion - Nasal cavity Nasal Cavity

* Respiratory epithelium everywhere except at the top (which has specialized ). * Serous and mucous glands and numerous blood vessels in lamina propria. * : midline structure consisting of bone and hyaline cartilage. * Nasal fossa: chambers on each side of septum. * NASAL CAVITIES - The nasal cavities are paired chambers separated by a bony and cartilaginous septum. • They are elongated spaces with a wide base and a narrow apex . • The skeletal framework is formed by bones and cartilages. • Each cavity communicates anteriorly with the external environment through the anterior nares (); - posteriorly with the nasopharynx through the choanae; and laterally with the and nasolacrimal duct. - The chambers are divided into three regions: • Nasal vestibule, is lined by skin • Respiratory region, (inferior two-thirds) of the nasal cavities and is lined by respiratory mucosa • Olfactory region, at the apex (upper one-third) of each nasal cavity and is lined by specialized * Respiratory Region of the Nasal Cavity - It is lined by the respiratory mucosa that contains a ciliated, pseudostratified columnar epithelium. - lamina propria is firmly attached to the periosteum and perichondrium . - The medial wall (the nasal septum) , is smooth, but the lateral walls are thrown into folds by the presence of three shelf-like, bony projections called conchae or turbinates. • The conchae play a dual role: - They increase surface area and - cause turbulence in airflow to allow conditioning of inspired air. - The ciliated, pseudostratified columnar epithelium is composed of five cell types: • Ciliated cells, tall columnar cells with cilia. • Goblet cells that synthesize and secrete mucus • Brush cells, bear short, blunt microvilli. • Small granule cells (Kulchitsky cells) that contain secretory granules (diffuse neuroendocrine system (DNES) • Basal cells, stem cells from which the other cell types arise * The mucosa of the respiratory region warms, moistens, and filters inspired air. - The lamina propria has a rich, a complex set of capillary loops. - The capillaries that reside near the surface are arranged in rows; . the blood flows perpendicular ( a mechanical heat exchange system). . These same vessels may become engorged and leaky during allergic reactions or viral infections such as the common cold. - Th e lamina propria contains mucous glands, many exhibiting serous demilunes. - the conchae (turbinates) increase the efficiency with which the inspired air is warmed. - The turbinates increase the efficiency of filtration through the process of turbulent precipitation. - The air stream is broken into eddies by the turbinates. * Olfactory Region of the Nasal Cavity - The olfactory region is located on part of the dome of each nasal cavity. - It is lined with a specialized olfactory mucosa. . Its slight yellowish brown color caused by pigment in the olfactory epithelium and the associated olfactory glands. . Its total surface area is only about 10 cm2 ; - in certain dog species have more than 150 cm2. - The olfactory epithelium, is also pseudostratified, contains very different cell types. . it lacks goblet cells. - The lamina propria is directly contiguous with the periosteum . . It contains numerous blood and lymphatic vessels, unmyelinated olfactory nerves, myelinated nerves, and olfactory glands. - The olfactory epithelium is composed of the following cell types: • cells are bipolar olfactory that span the thickness of the epithelium and enter the central nervous system. • Supporting or sustentacular cells are columnar cells that are similar to neuroglia cells and provide mechanical and metabolic support to the olfactory receptor cells. - They synthesize and secrete odorant-binding proteins. • Basal cells are stem cells from which new olfactory receptor cells and supporting cells differentiate. • Brush cells are the same cell type that occurs in the respiratory epithelium. - The olfactory epithelium is composed of the following cell types: • Olfactory receptor cells are bipolar olfactory neurons that span the thickness of the epithelium and enter the central nervous system. • Supporting or sustentacular cells are columnar cells that are similar to neuroglia cells and provide mechanical and metabolic support to the olfactory receptor cells. - They synthesize and secrete odorant-binding proteins. • Basal cells are stem cells from which new olfactory receptor cells and supporting cells differentiate. • Brush cells are the same cell type that occurs in the respiratory epithelium. * Olfactory receptor cells are bipolar neurons that possess an apical projection bearing cilia. - The apical domain of each olfactory receptor cell has a single dendritic process as a knob-like structure called the olfactory vesicle. .Thin cilia (10 to 23) with typical basal bodies arise from the olfactory vesicle and extend radially parallel to the surface. . up to 200 µm long and may overlap with cilia of adjacent . . The cilia are nonmotile, or have limited motility. - The basal domain of the cell gives rise to an unmyelinated axonal process . Collections of grouped into bundles that pass through a thin cribriform plate of the ethmoid bone, and finally entering the of the . . The collections of axons from olfactory receptor cells form the (cranial nerve I). - The olfactory axons are very fragile and can be harmed during traumatic head injury. . They can be permanently severed, resulting in anosmia (loss of the ). - The olfactory receptor cells have a life span of about 1 month. . If injured, they are quickly replaced. - Olfactory receptor cells (and some neurons of the enteric division ) are readily replaced during postnatal life. Olfactory mucosa of the nasal cavity. a. This diagram shows the three major cell types located within the olfactory epithelium: the olfactory cell, supporting (sustentacular) cell, and basal cell. The olfactory cell is the receptor cell; it has an apical expansion, the olfactory vesicle, from which long, nonmotile cilia extend. At its basal surface, it extends an into the connective tissue that joins with axons of other olfactory cells to form an olfactory nerve. The basal cells are small and cuboidal. They are restricted to the basal part of the epithelium. The supporting cells, in contrast, are columnar and extend the full thickness of the epithelium; their nuclei are located in the upper portion of the cell. Note the olfactory (Bowman’s) gland and its duct that empties on the surface of the mucosa. b. Photomicrograph of the olfactory mucosa. The olfactory epithelium exhibits nuclei through much of its thickness, but the individual cell types to which they belong are not discernible. The underlying connective tissue is largely occupied by numerous olfactory (Bowman’s) glands, olfactory nerves, and blood vessels. Note that the ducts of the olfactory glands extend from the secretory portion of the gland to the epithelial surface. 240. Diagram of olfactory transduction pathway. This diagram shows interactions of the odorant molecules with proteins associated with olfactory receptor cell. Incoming inhaled air odorant molecules are solubilized in the olfactory mucus and bind to olfactory binding proteins, which deliver them to the olfactory receptors. Note that different odorant molecules bind with different affinity to the olfactory receptors. Strong signal (see green G protein–coupled olfactory receptor) is produced by high affinity binding where odorant molecule (green) matches perfectly the binging site on the receptor. Other olfactory receptors (yellow and pink) show less affinity binding, thus producing weaker signals. Stimulated by odorant molecules, olfactory receptors activate enzyme adenylyl cyclase and initiate the cAMP cascade of events leading to the opening of specific Na+ and Ca2+ channels. Influx of Na+ and Ca2+ is responsible for cell depolarization. Generated action potential travels on axons of olfactory receptor cells from the nasal cavity, passing through the ethmoid bone and surrounding brain coverings to the olfactory bulb of the brain. * Paranasal Sinuses Paranasal sinuses are air-filled spaces in the bones of the walls of the nasal cavity. - The paranasal sinuses are extensions of the respiratory region of the nasal cavity and are lined by respiratory epithelium. - The sinuses are named for the bone in which they are found (i.e., the ethmoid, frontal, sphenoid, and maxillary bones). - The sinuses communicate with the nasal cavities via narrow openings onto the respiratory mucosa. - The mucosal surface of the sinuses is a thin, ciliated, pseudostratified columnar epithelium with numerous goblet cells. - Mucus produced in the sinuses is swept into the nasal cavities by coordinated ciliary movements. - The sinuses are often subject to acute infection after viral infection of the upper respiratory tract. Respiratory System

* Introduction * Conducting portion - Nasal cavity - Larynx * LARYNX - The passageway for air between the oropharynx and trachea is the larynx. - This complex tubular region of the respiratory system is formed by irregularly shaped plates of hyaline and elastic cartilage (the epiglottis and the vocal processes of the arytenoid cartilages). - The larynx serves as a conduit for air, organ for producing sounds. Epiglottis covers laryngeal opening during Laryngeal cartilages swallowing. support the wall of the Core of elastic cartilage. larynx and serve as Superior surface: attachments for vocalis nonkeratinized stratified muscles. squamous epithelium. Inferior surface: respiratory epithelium False vocal folds are covered by respiratory epithelium Vocal folds are covered by nonkeratinized stratified squamous epithelium

Larynx and epiglottis False vocal folds

True vocal folds Vestibule

Vocalis muscle

Larynx, coronal section Larynx: true and false vocal cords Trachea * The trachea is a short, flexible, air tube about 2.5 cm in diameter and about 10 cm long. * Extends from larynx and divides into two primary bronchi. * Contains 16-20 C-shaped hyaline cartilage rings with the dorsal opening bridged by smooth muscle (trachealis muscle). * Lined by respiratory epithelium. * Seromucous glands in lamina propria and submucosa. Trachea divides into 2 primary bronchi.

Trachea Respiratory Epithelium Cell Types

- Ciliated columnar cells: most abundant cell type. Cilia beat in unison and move mucus and trapped particles to oropharynx, where it is swallowed or expectorated. - Goblet cells: produce mucus. - Basal cells: stem cells that replenish epithelium. Hard to see. - Brush cells: Columnar cells. No cilia but have apical microvilli. Hard to see. - Neuroendocrine cells: Small granule cells (Kulchitsky cells) epithelial cells containing hormones. Hard to see. Photomicrograph of tracheal epithelium. Three major cell types are evident in the tracheal epithelium (Ep): ciliated columnar cells; mucus- secreting goblet cells (G) interspersed between the ciliated cells; and basal cells, which are close to the basement membrane (BM). The ciliated columnar cells extend from the basement membrane to the surface. At their free surface, they contain numerous cilia that, together, give the surface a brush-like appearance. At the base of the cilia is a dense eosinophilic line. This is owing to the linear aggregation of structures referred to as basal bodies, located at the proximal end of each cilium. Although basement membranes are not ordinarily seen in H&E preparations, a structure identified as such is seen regularly under the epithelium in the human trachea. The underlying lamina propria (LP) consists of loose connective tissue. The more deeply located submucosa (SM) contains dense irregular connective tissue with blood and lymphatic vessels, nerves, and numerous mucus-secreting tracheal glands. X 400. Trachea: respiratory epithelium Electron micrograph of human trachea. This electron micrograph shows the three main cell types of this respiratory epithelium. They are represented by ciliated epithelial cells extending to the surface, where they possess cilia; goblet cells with mucinogen granules; and basal cells, which are confined to the basal portion of the epithelial layer near the connective tissue. X1,800. (Courtesy of Dr. Johannes A. G. Rhodin.) * BRONCHI - The trachea divides into two main (primary) bronchi. - Anatomically, these divisions are more frequently described as simply the right and left main bronchi. . The right bronchus is wider and significantly shorter than the left. - On entering the hilum of the lung, each main bronchus divides into the lobar bronchi (secondary bronchi). - The right bronchus divides into three lobar bronchial branches and the left into two lobar bronchial branches, with each branch supplying one lobe. - The lobar bronchi give rise to 10 segmental bronchi ( tertiary bronchi); - The lobar bronchi of the left lung give rise to 8 segmental bronchi. Morphologic Changes as Bronchi Branch

* As branching progresses: - Connective tissue decreases in thickness - Relative amount of smooth muscle and elastic tissue increases - Cartilage disappears (gone by bronchioles) Lung super low-power view Bronchus Wall of Bronchus

- Respiratory epithelium (E) - Lamina propria (LP) - Smooth muscle (SM) - Submucosa - Hyaline cartilage (C) - Nerves (N) and blood vessels (V)

Note the order of structures: E → LP → SM → C Pseudostratified Goblet cells columnar epithelium

Cilia

Bronchus: respiratory epithelium Bronchioles * NO glands or cartilage. * Larger bronchioles have respiratory epithelium. * Smaller bronchioles have low columnar epithelium. * In asthma, the smooth muscle in the bronchioles constricts, causing difficulty breathing. Fibrous connective tissue is Respiratory present but epithelium is no cartilage folded or glands!

Smooth muscle

Bronchiole Smaller bronchioles have simple columnar epithelium Terminal Bronchioles

* Simple cuboidal epithelium with cilia. * Also: Clara cells (non-ciliated epithelial cells with secretory granules). * No goblet cells. * As you go down the respiratory tract, goblet cells are lost before cilia. Photomicrograph showing the respiratory portion of the bronchial tree. In this photomicrograph, a terminal bronchiole (TB) is shown longitudinally sectioned as it branches into two respiratory bronchioles (RB). The terminal bronchiole is the most distal part of the conducting portion of the respiratory system and is not engaged in gas exchange. The respiratory bronchiole engages in gas exchange and is the beginning of the respiratory portion of the bronchial tree. Respiratory bronchioles give rise to alveolar ducts (AD), which are elongate airways that have almost no walls, only alveoli surrounding the duct space. Alveolar sacs (AS) are spaces at the termination of the alveolar ducts that, likewise, are surrounded by alveoli. X120. Light micrograph of a 1 14m thick plastic section, stained with toluidine blue, showing a respiratory bronchiole with non-ciliated, dense-granulated cells (arrows). Serous-like cells containing relatively large dense granules are indicated by the "solid" arrows. The "open" arrow indicates a typical Clara cell containing fewer dense secretory granules at its protruding apex. (Scale bar•S 14m) Clara cells

Make surfactant components, break down mucus, detoxify harmful substances, transfer IgA, fight bacteria produce a 16 kDa protein known as Clara cell secretory protein (CC16). Diagram of a terminal bronchiolar epithelium. This diagram shows several cells found in the respiratory epithelium. The Clara cell, as illustrated here, is interposed between the brush cell and the small granule cell. The Clara cell is a nonciliated cell that has rounded apical surface, well-developed basal rER and Golgi apparatus and contains secretory vesicles filled with a surface-active agent. Adjacent, is the brush cell containing blunt microvilli, which are distinctive features of this cell. Cytoplasm of the brush cell shows a Golgi apparatus, lysosomes, mitochondria, and glycogen inclusions. A small granule cell is shown located between the Clara cell and ciliated cell. This cell contains small secretory vesicles, most of which are in the basal portion of the cell. In addition to the vesicles, the most conspicuous organelles of this cell are rER, a Golgi apparatus, and mitochondria. A nerve terminal is shown within the epithelium. Scanning electron micrograph of a terminal bronchiole. This scanning photomicrograph shows a longitudinal section throughout the terminal bronchiole and surrounding alveoli (A). Note that the apical surfaces of the Clara cells possess no cilia and have a characteristic dome- shaped appearance. 150. The inset shows some of the Clara cells at a higher magnifi cation and the cilia of a neighboring ciliated cell, which are present in very small numbers at this level. Note the relatively few cilia present on these small cells. X1,200. Airways Preceding Alveoli

* Respiratory bronchioles - As you go distally along the respiratory bronchioles, alveoli increase in number. - Cilia are gone by the end of the respiratory bronchiole. * Alveolar ducts - Back-to-back alveolar openings along wall - Smooth muscle between alveolar openings looks like knobs Respiratory bronchiole Alveolar duct Alveolar duct (AD), alveolar sac (AS) and alveolus (A) * Alveoli . - About 150 to 250 million alveoli are found in each adult lung; - their combined internal surface area is approximately 75 m2. Alveoli

* Sac-like structures with super-thin walls so O2 and CO2 can diffuse between air and blood. * Separated by interalveolar septae, which contain capillaries. * Cells lining interalveolar septae: - Type I cells (thin, flat squamous cells) - Type II cells (pneumocytes): produce surfactant - Brush cells are also present in the alveolar wall(few in number). Alveolus Type I Cells

* Cover 95% of alveolar surface, comprise only 40% of the entire alveolar lining cells * Simple squamous cells with thin cytoplasm * Blood-air barrier includes (from air to blood): - Type I cells - Fused basal laminae of type I cells and capillary endothelial cells - Capillary endothelial cells Type II Cells (Pneumocytes)

* Cover 5% of alveolar surface, account for 60% of the alveolar lining cells * Large cuboidal cells with round nuclei. * Typical secretory cell structure. - Lamellar bodies in cytoplasm rich in a mixture of phospholipids, neutral lipids, and proteins that form and store surfactant. * Surfactant decreases surface tension in alveoli and prevents collapse of alveoli during expiration. Alveoli lined by type I and II cells Electron micrograph of lung alveoli. This electron micrograph shows two alveolar spaces separated by an alveolar septum containing capillaries, some of which contain red blood cells. Note the areas of thin and thick portions of the alveolar septum. These are shown at a higher magnification in Figure 19.19. 5,800. Inset. Photomicrograph of an alveolus for comparison with the alveolar wall as seen in an electron micrograph. Arrows indicate alveolar capillaries containing red blood cells. X480. Electron micrograph of a type II alveolar cell. The type II alveolar cell has a dome-shaped apical surface with a number of short microvilli at its periphery and a relatively smooth-contoured apical center. The lateral cell margins are overlain to a variable degree by the type I alveolar cells that are joined to the type II cell by occluding junctions. Both cell types rest on the basal lamina (BL). The secretory vesicles (G ) in this specimen are largely dissolved, but their lamellar character is shown to advantage in Figure 19.17b. X24,000. Diagram of a type II alveolar cell and electron micrograph of lamellar bodies. a. Surfactant is an oily mixture of proteins, phospholipids, and neutral lipids that are synthesized in the rER from precursors in the blood. These precursors are glucose, fatty acids, choline, and amino acids. The protein constituents of surfactant are produced in the rER and stored in the cytoplasm within lamellar bodies, which are discharged into the lumen of the alveolus. With the aid of surfactant protein, surfactant is distributed on the surface of epithelial cells lining the alveolus as a thin film that reduces the surface tension. b. Higher magnification electron micrograph showing the typical lamellar pattern of the secretory vesicles of type II alveolar cells. These vesicles contain the pulmonary surfactant precursor proteins. X38,000. ( Courtesy of Dr. A. Mercuri.) * Surfactant decreases the alveolar surface tension and actively participates in the clearance of foreign materials. - The most specific phospholipid called dipalmitoylphosphatidylcholine (DPPC), which accounts for almost all surface tension. - Surfactant synthesis in the fetus occurs after the 35th week of gestation and is modulated by a variety of hormones, including; . Cortisol, insulin, prolactin, and thyroxine. * Surfactant proteins help organize the surfactant layer and modulate alveolar immune responses. - The hydrophobic proteins are necessary for the structure and function of surfactant. - These proteins are listed here: • Surfactant protein A (SP-A), the most abundant surfactant protein. - It modulates immune responses to viruses, bacteria, and fungi. • Surfactant protein B (SP-B), an important protein for the transformation of the lamellar body into the thin surface film of surfactant. • Surfactant protein C (SP-C), maintenance of the thin film layer within the alveoli. • Surfactant protein D (SP-D), a primary protein involved in host defense. - It binds to various microorganisms (e.g., Gram-negative bacteria) and to lymphocytes. - SP-D participates in a local inflammatory response to acute lung injury and with SP-A modulates an allergic response to various inhaled antigens. * The alveolar septum is the site of the air–blood barrier. - The air–blood barrier refers to the cells and cell products across which gases must diffuse between the alveolar and capillary compartments. - The thinnest air–blood barrier consists of . a thin layer of surfactant, . a type I epithelial cell and its basal lamina, and . a capillary endothelial cell and its basal lamina. - Often, these two basal laminae are fused. - Connective tissue cells and fibers that may be present between the two basal laminae. - These two arrangements produce a thin portion and a thick portion of the barrier. - Most gas exchange occurs across the thin portion of the barrier. . The thick portion is thought to be a site in which tissue fluid can accumulate and even cross into the alveolus. - Lymphatic vessels in the connective tissue of the terminal bronchioles drain fluid that accumulates in the thick portion of the septum. Diagram of the interalveolar septum. This diagram shows the thick and thin portions of the interalveolar septum. The thin portion forms the air–blood barrier and is responsible for most of the gas exchange that occurs in the lung. Arrows indicate the direction of CO2 and O2 exchange between the alveolar air space and the blood. The thick portion of the interalveolar septum plays an important role in fluid distribution and its dynamics. It contains connective tissue cells. Note the macrophage in the thick portion that extends its processes into the lumen of the alveolus. Electron micrograph of the alveolar septum. This high-magnification micrograph shows the thin portion of the air– blood barrier where it consists of type I alveolar cells, capillary endothelium, and the fused basal lamina shared by both cells. In the thick portion, the type I alveolar cell (arrows) rests on a basal lamina, and on the opposite side is connective tissue in which collagen fibrils and elastic fibers are evident. X33.000 Alveolar Macrophages (Dust Cells)

* Found on surface of alveoli, within alveoli and in interstitial connective tissue. * Remove debris and particles that escape mucus and cilia in conducting portion of respiratory tract Macrophages (dust cells) Pleura Parietal and Visceral Pleura

* The outer surface of the lung and the inner surface of the thoracic cavity are covered by the pleura, which is a serous membrane (serosa). * Parietal pleura lines the thoracic cavity; * visceral pleura covers the lungs. * Serous membranes consist of simple squamous epithelial cells called mesothelium plus a thin layer of connective tissue. * The pleural cavity contains serous fluid made by the pleura.