- Email: [email protected]
Trachea
Tr a c h e a : Anatomy and Physiology Beate E.M. Brand-Saberia,*, Thorsten Schäferb KEYWORDS Macroscopic and microscopic anatomy Morphogenesis Tracheal stem cells Physiology Function
KEY POINTS The trachea is a tube made up of cartilage, connective tissue, smooth muscle, and a mucosal layer connecting the larynx to the principal bronchi and finally to the lungs. The tracheal mucosa consists of a pseudostratified columnar epithelium with kinocilia and goblet cells, supported by a lamina propria containing tracheal glands. Morphogenesis of the trachea depends on epithelial-mesenchymal interactions of the endodermal trachea and the mesoderm-derived mesenchyme surrounding it. The mucosal epithelium and the ducts of the tracheal glands contain different types of stem cells. The main functions of the trachea comprise air flow into the lungs, mucociliary clearance, and humidification and warming of the air.
The trachea (windpipe) is a semiflexible tube of 1.5 to 2 cm in width and 10 to 13 cm in length, reaching from the lower portion of the larynx approximately at the level of the sixth to seventh cervical vertebra to the fourth to fifth thoracic vertebra, where it bifurcates to form the two bronchi for the lungs. The tracheal wall consists of up to 20 incomplete rings of hyaline cartilage forming the anterior and lateral circumference, and smooth muscle at the posterior side, which are both embedded into a fibrous membrane of elastic connective tissue (Fig. 1). The muscle contains transverse and longitudinal fibers; the transverse fibers connect the ends of the cartilaginous rings posteriorly and are termed m. trachealis. Seromucinous tracheal glands are located in the connective tissue between the epithelial layer and the cartilage, sometimes also on the outer side, and are found abundantly exterior to the tracheal muscle. The function of the glands that open via ducts on the
inner surface of the trachea is to lubricate the inner lining of the trachea. The epithelium consists of a pseudostratified columnar epithelium with kinocilia and goblet cells that also produce a mucous film (Fig. 2). The direction of the beat of the kinocilia toward the larynx results in the transport of particulates and cell detritus away from the lungs and its elimination from the body.
MORPHOGENESIS OF THE TRACHEA During the fourth week of development, the trachea develops initially from the ventral foregut epithelium forming the tracheobronchial diverticulum, and grows caudally before branching into the lung buds that will later elongate to form the principal bronchi. The inner lining of the trachea is thus of endodermal origin. However, it is an excellent example of epithelial-mesenchymal interactions that occur commonly during organogenesis, because the endodermal tube undergoes morphogenetic movements such as growth and branching
The authors have nothing to disclose. a Department of Anatomy and Molecular Embryology, Institute of Anatomy, Ruhr University Bochum, Universitaetsstrasse 150, Bochum 44801, Germany; b Helios Klinik Hagen-Ambrock, Institute of Clinical Physiology, Institute of Physiology, Ruhr University Bochum, Universitaetsstrasse 150, Bochum 44801, Germany * Corresponding author. E-mail address: [email protected] Thorac Surg Clin 24 (2014) 1–5 http://dx.doi.org/10.1016/j.thorsurg.2013.09.004 1547-4127/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
thoracic.theclinics.com
ANATOMIC OVERVIEW OF THE TRACHEA
2
Brand-Saberi & Scha¨fer RECENT HISTOLOGIC FINDINGS
Fig. 1. Transverse section of a human trachea with fibromuscular portion (paries membranaceus; 1) and tracheal cartilage (3); the seromucinous tracheal glands (2) are located in the connective tissue subjacent to the inner lining. The tunica mucosa (4) consists of the pseudostratified columnar epithelium shown in Fig. 2, and the lamina propria. The tunica adventitia is labeled as 5. (Azan staining, original magnification 40).
only under the influence of the surrounding splanchnic mesoderm (Fig. 3). The interactions are based on signals from the major signaling pathways such as fibroblast growth factor 10, Sprouty, epidermal growth factor, insulin-like growth factor, hepatocyte growth factor, and transcription factors.1 During the fourth week of development, the trachea branches to form the right and the left lung bud. The development of the trachea thus forms the prerequisite for the formation of the lungs by repeated rounds of bifurcation events (Fig. 4).
A detailed analysis of the pseudostratified mucosal epithelium of the trachea has revealed the presence of several highly specialized and less welldefined cell types. The most common distinction is made between the “brush cells” and the neuroendocrine cells resembling the enteroendocrine cells of the gastrointestinal tract, neuroendocrine cells being dispersed in the respiratory epithelium. The function of the neuroendocrine cells in the respiratory tract is currently under debate; mechanosensitive functions and O2-sensing functions2 have been suggested. In contrast to the enteroendocrine cells, the chemosensory function of the neuroendocrine cells in the respiratory tract has not yet been proved. The non-neuroendocrine cells of the respiratory tract have been termed brush cells, and are solitary chemosensory cells in the upper airways. Surprisingly, cells expressing the molecular components of the taste transduction pathway display the ultrastructural morphology of the brush cells.3 The term brush cell reflects the presence of apical microvilli containing villin and fimbrin.4 Recently, cholinergic chemosensory cells have been described in the trachea5–7 by expression of relevant receptors and components of the bitter taste transduction pathway. These cells are connected to afferent fibers of the vagal nerve via nicotinic acetylcholine receptors. These cholinergic brush cells were demonstrated to affect the control of breathing,5 and are thus functional in safeguarding the lower airways by sensing the composition of the luminal fluid inside the trachea and the bronchi.
TRACHEAL STEM CELLS
Fig. 2. Detail of the tracheal wall showing (1) the ciliated pseudostratified columnar epithelium, (2) elastic fibers of the lamina propria, tracheal glands with serous (3) and mucinous (4) acini, and (5) hyaline tracheal cartilage. (Goldner staining, original magnification 200).
As the epithelium of the airways is exposed to the environment with the risk of injury, it must be able to physiologically regenerate. During this process, a subpopulation of the basal cells in the pseudostratified columnar epithelium is activated, and replaces the sloughed or injured surface cells.8–10 The stem/progenitor cells can be characterized by the presence of transcription factor Trp-63 (p63) and cytokeratins 5 and 14.11 Trp-63 is involved in the development of the respiratory and other epithelia, in particular the establishment of the basal cells.12 In contrast to rodents in which these stem/progenitor cells are only present in the trachea, in humans they occur throughout the respiratory tract, including the small bronchi. Basal cells can develop into ciliated surface cells and Clara cells which, as Clara cells give rise to goblet cells, can be considered multipotent.
Trachea
Fig. 3. Ventral view of embryonic trachea and lung development. The endodermal lining of the tracheobronchial diverticulum is depicted in light brown and the splanchnic mesoderm surrounding it is depicted in gray. Growth and bifurcations occur in a sequence of epithelial-mesenchymal interactions involving signaling molecules and transcription factors. Lung development thus depends on the formation of the tracheobronchial bud, and occurs in several phases (embryonic, pseudoglandular, canalicular). (Courtesy of Helga Schulze, Bochum, Germany.)
Despite early reports and a long history during which stem/progenitor cells had already been described in the seromucinous glands lining the airways,13,14 more recently a new type of stem/ progenitor cell has been described in the trachea of the mouse,15 which is localized in the ducts of the tracheal glands. The gland duct cells have been isolated and shown to be multipotent stem/ progenitor cell populations for the murine airway epithelium that can give rise to serous and mucous tubules, duct cells, and ciliated surface epithelium. What makes them unique is their capability to survive severe hypoxic-ischemic injury. Although the situation differs between mouse and humans,14,16 these findings contribute important insights into the physiology of the tracheal epithelium, in particular in the pathologic setting.
PHYSIOLOGIC OVERVIEW OF THE TRACHEA The trachea Conducts air between the larynx and the bronchi Exchanges heat and moisture Removes particles
AIR TRANSPORT IN THE TRACHEA The transport of air is critically dependent on the inner diameter of the trachea. The resistance to flow through a tube, represented by the law of Hagen-Poiseuille, is inversely proportional to the radius of the tube raised to the fourth power, as long as the flow is laminar. At higher flow rates the flow may become turbulent, which further increases the resistance (Fig. 5). Mucosal swelling, constriction of airway muscles, or tumors that reduce the airway space, but also endotracheal tubes, considerably increase the resistance to airflow: a 50% reduction of the inner diameter increases the resistance 16-fold, and during turbulent flow up to 32-fold.17
AIR CONDITIONING
Fig. 4. Frontal section of a human embryo of 22.5 mm (Carnegie stage 21). The trachea (1) with cartilage blastemas (2) has divided into the right (3) and the left (4) principal bronchus. (5) indicates the developing left lung, and (6) the developing right lung. (Hematoxylin-eosin staining, original magnification 40). (Courtesy of Professor Dr Klaus Hinrichsen, Bochum, Germany.)
During inspiration the upper airways warm and humidify the inspired air. This process is very efficient. During quiet breathing at room temperature, air is completely warmed up to 37 C and humidified to 100% saturation shortly distal of the bifurcation; this is called the isothermal saturation point. The drier and colder the inspired air is, the more this point moves to the lung periphery, inducing dehydration and cooling of the lung tissue.18 Extreme mountaineering or mountain biking, for example, combines inspiration of cold and dry air with high levels of minute ventilation, leading to stress on the lung tissue. In addition,
3
4
Brand-Saberi & Scha¨fer the epithelium and the environment. This secretion is largely controlled by the autonomic nervous system, modulated by numerous inflammatory mediators.20 These mediators form 2, possibly 3, layers: a sol layer is next to the epithelium, making ciliary beating possible. The sol layer is covered by the mucus or gel layer, possibly separated by a layer of surfactant. The mucus collects debris and microorganisms, and is transported orally by the mechanical forces of coordinated ciliary beating and the airflow during expiration. Mucus production and mucociliary transport capacity are higher in the small airways than in the central airways, where transport by expiratory airflow is higher.21 This airflow transport mainly depends on the airflow velocity during expiration, determined by the airway diameter and the difference between intrapulmonary and ambient pressure. The mucus viscosity varies depending on shear forces, and may decrease by a factor of up to 500 during coughing, which is explained by a realignment of macromolecules by the applied force.21 Nishino and colleagues22 found at least 6 different responses to stimulation of tracheal mucosa by injection of distilled water, examined under different levels of enflurane anesthesia: Fig. 5. Effect of reduction of the tube diameter on the flow rate (at constant pressures) according to the law of Hagen-Poiseuille. Halving of the diameter of a tube (A) reduces the flow rate to 1/16 under the conditions of laminar flow (B) and to 1/32 during turbulent flow (C).
however, bypassing the upper airways with a tracheostomy or endotracheal tubes may lead to cooling and drying of lung tissue, unless the inspired air is warmed and humidified.17 Room air at a temperature of 22 C and 50% relative humidity approximately contains 10 mg/L H2O and will have absorbed an additional 34 mg/L at the isothermal saturation point. Expired air cools down to approximately 32 C at the nostrils and still contains 34 mg/L moisture at 100% relative humidity. This amount causes a daily water loss of at least 240 mL as part of the “perspiratio insensibilis,” the unnoticed loss of fluid via the skin and the lungs. The energy requirement to compensate for evaporative cooling equals approximately 600 kJ per day, which is about 10% of the total heat production of the body.19
Cough reflex (most sensitive) Apneic reflex (most resistant to deepening anesthesia) Expiration reflex Spasmodic, panting breathing Slowing of breathing Rapid shallow breathing A cough begins with a closure of the glottis, followed by an isometric contraction of the expiratory muscles, which generates a high intrathoracic pressure. Sudden opening of the glottis creates a burst of expiratory airflow, transporting mucus orally. Huffs have a similar effect on mucus transport. Huffs start with a fast, dynamic expiration. The glottis remains open throughout the maneuver.21 In conclusion, the functions of the trachea by far exceed the simple conduction of air between the larynx and the lungs: The trachea plays an important role in the protection of the sensitive lung tissue from injuries and invasion by microorganisms. Pathologic or iatrogenic restrictions of the tracheal lumen severely increase the airway resistance and, thus, the patient’s work of breathing.
REMOVAL OF INSPIRED DEBRIS AND ASPIRATED MICROORGANISMS
ACKNOWLEDGMENTS
Tracheobronchial glands produce a mucin-rich secretion that forms a protective barrier between
The authors wish to thank Annegrit Schlichting and Asta Schiffgen for excellent technical support,
Trachea Helga Schulze for art work, and Abdulatif Al Haj, M.Sc., for photographs of histologic sections. 12.
REFERENCES 1. Warburton D, Schwarz M, Tefft D, et al. The molecular basis of lung morphogenesis. Mech Dev 2000; 92:55–81. 2. Cutz E, Yeger H, Pan J. Pulmonary neuroendocrine cell system in pediatric lung disease—recent advances. Pediatr Dev Pathol 2007;10(6):419–35. 3. Merigo F, Benati D, Tizziano M, et al. a-Gustducin immunoreactivity in the airways. Cell Tissue Res 2005;319(2):211–9. 4. Ho¨fer D, Drenckhahn D. Identification of brush cells in the alimentary and respiratory system by antibodies to villin and fimbrin. Histochemistry 1992; 98(4):237–42. 5. Kummer W, Lips KS, Pfeil U. The epithelial cholinergic system of the airways. Histochem Cell Biol 2008;130(2):219–34. 6. Krasteva G, Canning BJ, Hartmann P, et al. Cholinergic chemosensory cells in the trachea regulate breathing. Proc Natl Acad Sci U S A 2011;108(23): 9478–83. 7. Krasteva G, Kummer W. “Tasting” the airway lining fluid. Histochem Cell Biol 2012;138:365–83. 8. Schoch KG, Lori A, Burns KA, et al. A subset of mouse tracheal epithelial basal cells generates large colonies in vitro. Am J Physiol Lung Cell Mol Physiol 2004;286:L631–42. 9. Hong KU, Reynolds SD, Watkins S, et al. Basal cells are a multipotent progenitor capable of renewing the bronchial epithelium. Am J Pathol 2004;164:577–88. 10. Hong KU, Reynolds SD, Watkins S, et al. In vivo differentiation potential of tracheal basal cells: evidence for multipotent and unipotent subpopulations. Am J Physiol Lung Cell Mol Physiol 2004; 286:L643–9. 11. Rock JR, Onaitis MW, Rawlins EL, et al. Basal cells as stem cells of the mouse trachea and human
13.
14.
15.
16.
17. 18.
19.
20.
21. 22.
airway epithelium. Proc Natl Acad Sci U S A 2009; 106:12771–5. Daniely Y, Liao G, Dixon D, et al. Critical role of p63 in the development of a normal esophageal and tracheobronchial epithelium. Am J Physiol Cell Physiol 2004;287:C171–81. Engelhart JF, Schlossberg H, Yankaskas JR, et al. Progenitor cells of the adult human airway involved in submucosal gland development. Development 1995;121:2031–46. Liu XM, Engelhardt JF. The glandular stem/progenitor cell niche in airway development and repair. Proc Am Thorac Soc 2008;5:682–8. Hegab A, Ha VL, Gilbert JL, et al. Novel stem/ progenitor cell population from murine tracheal submucosal gland ducts with multipotent regenerative potential. Stem Cells 2011;29: 1283–93. Rock JR, Randell SH, Hogan BL. Airway basal stem cells: a perspective on their roles in epithelial homeostasis and remodelling. Dis Model Mech 2010; 3:545–56. Epstein SK. Anatomy and physiology of tracheostomy. Respir Care 2005;50:476–82. Kandjov IM. Heat and water rate transfer processes in the human respiratory tract at various altitudes. J Theor Biol 2001;208:287–93. Sedlacek B. Die Befeuchtungsleistung hydrophober Heat und Moisture Exchanger (HME) unter klinischen Bedingungen. Dissertation. Charite´ – Universita¨tsmedizin Berlin. Berlin: Klinik fu¨r Ana¨sthesiologie und Operative Intensivmedizin; 2006. Finkbeiner WE. Physiology and pathology of tracheobronchial glands. Respir Physiol 1999;118: 77–83. van der Schans CP. Bronchial mucus transport. Respir Care 2007;52:1150–6. Nishino T, Hiraga K, Tadanobu M, et al. Respiratory reflex responses to stimulation of tracheal mucosa in enflurane-anesthetized humans. J Appl Phys 1988; 65:1069–74.
5
KEY POINTS The trachea is a tube made up of cartilage, connective tissue, smooth muscle, and a mucosal layer connecting the larynx to the principal bronchi and finally to the lungs. The tracheal mucosa consists of a pseudostratified columnar epithelium with kinocilia and goblet cells, supported by a lamina propria containing tracheal glands. Morphogenesis of the trachea depends on epithelial-mesenchymal interactions of the endodermal trachea and the mesoderm-derived mesenchyme surrounding it. The mucosal epithelium and the ducts of the tracheal glands contain different types of stem cells. The main functions of the trachea comprise air flow into the lungs, mucociliary clearance, and humidification and warming of the air.
The trachea (windpipe) is a semiflexible tube of 1.5 to 2 cm in width and 10 to 13 cm in length, reaching from the lower portion of the larynx approximately at the level of the sixth to seventh cervical vertebra to the fourth to fifth thoracic vertebra, where it bifurcates to form the two bronchi for the lungs. The tracheal wall consists of up to 20 incomplete rings of hyaline cartilage forming the anterior and lateral circumference, and smooth muscle at the posterior side, which are both embedded into a fibrous membrane of elastic connective tissue (Fig. 1). The muscle contains transverse and longitudinal fibers; the transverse fibers connect the ends of the cartilaginous rings posteriorly and are termed m. trachealis. Seromucinous tracheal glands are located in the connective tissue between the epithelial layer and the cartilage, sometimes also on the outer side, and are found abundantly exterior to the tracheal muscle. The function of the glands that open via ducts on the
inner surface of the trachea is to lubricate the inner lining of the trachea. The epithelium consists of a pseudostratified columnar epithelium with kinocilia and goblet cells that also produce a mucous film (Fig. 2). The direction of the beat of the kinocilia toward the larynx results in the transport of particulates and cell detritus away from the lungs and its elimination from the body.
MORPHOGENESIS OF THE TRACHEA During the fourth week of development, the trachea develops initially from the ventral foregut epithelium forming the tracheobronchial diverticulum, and grows caudally before branching into the lung buds that will later elongate to form the principal bronchi. The inner lining of the trachea is thus of endodermal origin. However, it is an excellent example of epithelial-mesenchymal interactions that occur commonly during organogenesis, because the endodermal tube undergoes morphogenetic movements such as growth and branching
The authors have nothing to disclose. a Department of Anatomy and Molecular Embryology, Institute of Anatomy, Ruhr University Bochum, Universitaetsstrasse 150, Bochum 44801, Germany; b Helios Klinik Hagen-Ambrock, Institute of Clinical Physiology, Institute of Physiology, Ruhr University Bochum, Universitaetsstrasse 150, Bochum 44801, Germany * Corresponding author. E-mail address: [email protected] Thorac Surg Clin 24 (2014) 1–5 http://dx.doi.org/10.1016/j.thorsurg.2013.09.004 1547-4127/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
thoracic.theclinics.com
ANATOMIC OVERVIEW OF THE TRACHEA
2
Brand-Saberi & Scha¨fer RECENT HISTOLOGIC FINDINGS
Fig. 1. Transverse section of a human trachea with fibromuscular portion (paries membranaceus; 1) and tracheal cartilage (3); the seromucinous tracheal glands (2) are located in the connective tissue subjacent to the inner lining. The tunica mucosa (4) consists of the pseudostratified columnar epithelium shown in Fig. 2, and the lamina propria. The tunica adventitia is labeled as 5. (Azan staining, original magnification 40).
only under the influence of the surrounding splanchnic mesoderm (Fig. 3). The interactions are based on signals from the major signaling pathways such as fibroblast growth factor 10, Sprouty, epidermal growth factor, insulin-like growth factor, hepatocyte growth factor, and transcription factors.1 During the fourth week of development, the trachea branches to form the right and the left lung bud. The development of the trachea thus forms the prerequisite for the formation of the lungs by repeated rounds of bifurcation events (Fig. 4).
A detailed analysis of the pseudostratified mucosal epithelium of the trachea has revealed the presence of several highly specialized and less welldefined cell types. The most common distinction is made between the “brush cells” and the neuroendocrine cells resembling the enteroendocrine cells of the gastrointestinal tract, neuroendocrine cells being dispersed in the respiratory epithelium. The function of the neuroendocrine cells in the respiratory tract is currently under debate; mechanosensitive functions and O2-sensing functions2 have been suggested. In contrast to the enteroendocrine cells, the chemosensory function of the neuroendocrine cells in the respiratory tract has not yet been proved. The non-neuroendocrine cells of the respiratory tract have been termed brush cells, and are solitary chemosensory cells in the upper airways. Surprisingly, cells expressing the molecular components of the taste transduction pathway display the ultrastructural morphology of the brush cells.3 The term brush cell reflects the presence of apical microvilli containing villin and fimbrin.4 Recently, cholinergic chemosensory cells have been described in the trachea5–7 by expression of relevant receptors and components of the bitter taste transduction pathway. These cells are connected to afferent fibers of the vagal nerve via nicotinic acetylcholine receptors. These cholinergic brush cells were demonstrated to affect the control of breathing,5 and are thus functional in safeguarding the lower airways by sensing the composition of the luminal fluid inside the trachea and the bronchi.
TRACHEAL STEM CELLS
Fig. 2. Detail of the tracheal wall showing (1) the ciliated pseudostratified columnar epithelium, (2) elastic fibers of the lamina propria, tracheal glands with serous (3) and mucinous (4) acini, and (5) hyaline tracheal cartilage. (Goldner staining, original magnification 200).
As the epithelium of the airways is exposed to the environment with the risk of injury, it must be able to physiologically regenerate. During this process, a subpopulation of the basal cells in the pseudostratified columnar epithelium is activated, and replaces the sloughed or injured surface cells.8–10 The stem/progenitor cells can be characterized by the presence of transcription factor Trp-63 (p63) and cytokeratins 5 and 14.11 Trp-63 is involved in the development of the respiratory and other epithelia, in particular the establishment of the basal cells.12 In contrast to rodents in which these stem/progenitor cells are only present in the trachea, in humans they occur throughout the respiratory tract, including the small bronchi. Basal cells can develop into ciliated surface cells and Clara cells which, as Clara cells give rise to goblet cells, can be considered multipotent.
Trachea
Fig. 3. Ventral view of embryonic trachea and lung development. The endodermal lining of the tracheobronchial diverticulum is depicted in light brown and the splanchnic mesoderm surrounding it is depicted in gray. Growth and bifurcations occur in a sequence of epithelial-mesenchymal interactions involving signaling molecules and transcription factors. Lung development thus depends on the formation of the tracheobronchial bud, and occurs in several phases (embryonic, pseudoglandular, canalicular). (Courtesy of Helga Schulze, Bochum, Germany.)
Despite early reports and a long history during which stem/progenitor cells had already been described in the seromucinous glands lining the airways,13,14 more recently a new type of stem/ progenitor cell has been described in the trachea of the mouse,15 which is localized in the ducts of the tracheal glands. The gland duct cells have been isolated and shown to be multipotent stem/ progenitor cell populations for the murine airway epithelium that can give rise to serous and mucous tubules, duct cells, and ciliated surface epithelium. What makes them unique is their capability to survive severe hypoxic-ischemic injury. Although the situation differs between mouse and humans,14,16 these findings contribute important insights into the physiology of the tracheal epithelium, in particular in the pathologic setting.
PHYSIOLOGIC OVERVIEW OF THE TRACHEA The trachea Conducts air between the larynx and the bronchi Exchanges heat and moisture Removes particles
AIR TRANSPORT IN THE TRACHEA The transport of air is critically dependent on the inner diameter of the trachea. The resistance to flow through a tube, represented by the law of Hagen-Poiseuille, is inversely proportional to the radius of the tube raised to the fourth power, as long as the flow is laminar. At higher flow rates the flow may become turbulent, which further increases the resistance (Fig. 5). Mucosal swelling, constriction of airway muscles, or tumors that reduce the airway space, but also endotracheal tubes, considerably increase the resistance to airflow: a 50% reduction of the inner diameter increases the resistance 16-fold, and during turbulent flow up to 32-fold.17
AIR CONDITIONING
Fig. 4. Frontal section of a human embryo of 22.5 mm (Carnegie stage 21). The trachea (1) with cartilage blastemas (2) has divided into the right (3) and the left (4) principal bronchus. (5) indicates the developing left lung, and (6) the developing right lung. (Hematoxylin-eosin staining, original magnification 40). (Courtesy of Professor Dr Klaus Hinrichsen, Bochum, Germany.)
During inspiration the upper airways warm and humidify the inspired air. This process is very efficient. During quiet breathing at room temperature, air is completely warmed up to 37 C and humidified to 100% saturation shortly distal of the bifurcation; this is called the isothermal saturation point. The drier and colder the inspired air is, the more this point moves to the lung periphery, inducing dehydration and cooling of the lung tissue.18 Extreme mountaineering or mountain biking, for example, combines inspiration of cold and dry air with high levels of minute ventilation, leading to stress on the lung tissue. In addition,
3
4
Brand-Saberi & Scha¨fer the epithelium and the environment. This secretion is largely controlled by the autonomic nervous system, modulated by numerous inflammatory mediators.20 These mediators form 2, possibly 3, layers: a sol layer is next to the epithelium, making ciliary beating possible. The sol layer is covered by the mucus or gel layer, possibly separated by a layer of surfactant. The mucus collects debris and microorganisms, and is transported orally by the mechanical forces of coordinated ciliary beating and the airflow during expiration. Mucus production and mucociliary transport capacity are higher in the small airways than in the central airways, where transport by expiratory airflow is higher.21 This airflow transport mainly depends on the airflow velocity during expiration, determined by the airway diameter and the difference between intrapulmonary and ambient pressure. The mucus viscosity varies depending on shear forces, and may decrease by a factor of up to 500 during coughing, which is explained by a realignment of macromolecules by the applied force.21 Nishino and colleagues22 found at least 6 different responses to stimulation of tracheal mucosa by injection of distilled water, examined under different levels of enflurane anesthesia: Fig. 5. Effect of reduction of the tube diameter on the flow rate (at constant pressures) according to the law of Hagen-Poiseuille. Halving of the diameter of a tube (A) reduces the flow rate to 1/16 under the conditions of laminar flow (B) and to 1/32 during turbulent flow (C).
however, bypassing the upper airways with a tracheostomy or endotracheal tubes may lead to cooling and drying of lung tissue, unless the inspired air is warmed and humidified.17 Room air at a temperature of 22 C and 50% relative humidity approximately contains 10 mg/L H2O and will have absorbed an additional 34 mg/L at the isothermal saturation point. Expired air cools down to approximately 32 C at the nostrils and still contains 34 mg/L moisture at 100% relative humidity. This amount causes a daily water loss of at least 240 mL as part of the “perspiratio insensibilis,” the unnoticed loss of fluid via the skin and the lungs. The energy requirement to compensate for evaporative cooling equals approximately 600 kJ per day, which is about 10% of the total heat production of the body.19
Cough reflex (most sensitive) Apneic reflex (most resistant to deepening anesthesia) Expiration reflex Spasmodic, panting breathing Slowing of breathing Rapid shallow breathing A cough begins with a closure of the glottis, followed by an isometric contraction of the expiratory muscles, which generates a high intrathoracic pressure. Sudden opening of the glottis creates a burst of expiratory airflow, transporting mucus orally. Huffs have a similar effect on mucus transport. Huffs start with a fast, dynamic expiration. The glottis remains open throughout the maneuver.21 In conclusion, the functions of the trachea by far exceed the simple conduction of air between the larynx and the lungs: The trachea plays an important role in the protection of the sensitive lung tissue from injuries and invasion by microorganisms. Pathologic or iatrogenic restrictions of the tracheal lumen severely increase the airway resistance and, thus, the patient’s work of breathing.
REMOVAL OF INSPIRED DEBRIS AND ASPIRATED MICROORGANISMS
ACKNOWLEDGMENTS
Tracheobronchial glands produce a mucin-rich secretion that forms a protective barrier between
The authors wish to thank Annegrit Schlichting and Asta Schiffgen for excellent technical support,
Trachea Helga Schulze for art work, and Abdulatif Al Haj, M.Sc., for photographs of histologic sections. 12.
REFERENCES 1. Warburton D, Schwarz M, Tefft D, et al. The molecular basis of lung morphogenesis. Mech Dev 2000; 92:55–81. 2. Cutz E, Yeger H, Pan J. Pulmonary neuroendocrine cell system in pediatric lung disease—recent advances. Pediatr Dev Pathol 2007;10(6):419–35. 3. Merigo F, Benati D, Tizziano M, et al. a-Gustducin immunoreactivity in the airways. Cell Tissue Res 2005;319(2):211–9. 4. Ho¨fer D, Drenckhahn D. Identification of brush cells in the alimentary and respiratory system by antibodies to villin and fimbrin. Histochemistry 1992; 98(4):237–42. 5. Kummer W, Lips KS, Pfeil U. The epithelial cholinergic system of the airways. Histochem Cell Biol 2008;130(2):219–34. 6. Krasteva G, Canning BJ, Hartmann P, et al. Cholinergic chemosensory cells in the trachea regulate breathing. Proc Natl Acad Sci U S A 2011;108(23): 9478–83. 7. Krasteva G, Kummer W. “Tasting” the airway lining fluid. Histochem Cell Biol 2012;138:365–83. 8. Schoch KG, Lori A, Burns KA, et al. A subset of mouse tracheal epithelial basal cells generates large colonies in vitro. Am J Physiol Lung Cell Mol Physiol 2004;286:L631–42. 9. Hong KU, Reynolds SD, Watkins S, et al. Basal cells are a multipotent progenitor capable of renewing the bronchial epithelium. Am J Pathol 2004;164:577–88. 10. Hong KU, Reynolds SD, Watkins S, et al. In vivo differentiation potential of tracheal basal cells: evidence for multipotent and unipotent subpopulations. Am J Physiol Lung Cell Mol Physiol 2004; 286:L643–9. 11. Rock JR, Onaitis MW, Rawlins EL, et al. Basal cells as stem cells of the mouse trachea and human
13.
14.
15.
16.
17. 18.
19.
20.
21. 22.
airway epithelium. Proc Natl Acad Sci U S A 2009; 106:12771–5. Daniely Y, Liao G, Dixon D, et al. Critical role of p63 in the development of a normal esophageal and tracheobronchial epithelium. Am J Physiol Cell Physiol 2004;287:C171–81. Engelhart JF, Schlossberg H, Yankaskas JR, et al. Progenitor cells of the adult human airway involved in submucosal gland development. Development 1995;121:2031–46. Liu XM, Engelhardt JF. The glandular stem/progenitor cell niche in airway development and repair. Proc Am Thorac Soc 2008;5:682–8. Hegab A, Ha VL, Gilbert JL, et al. Novel stem/ progenitor cell population from murine tracheal submucosal gland ducts with multipotent regenerative potential. Stem Cells 2011;29: 1283–93. Rock JR, Randell SH, Hogan BL. Airway basal stem cells: a perspective on their roles in epithelial homeostasis and remodelling. Dis Model Mech 2010; 3:545–56. Epstein SK. Anatomy and physiology of tracheostomy. Respir Care 2005;50:476–82. Kandjov IM. Heat and water rate transfer processes in the human respiratory tract at various altitudes. J Theor Biol 2001;208:287–93. Sedlacek B. Die Befeuchtungsleistung hydrophober Heat und Moisture Exchanger (HME) unter klinischen Bedingungen. Dissertation. Charite´ – Universita¨tsmedizin Berlin. Berlin: Klinik fu¨r Ana¨sthesiologie und Operative Intensivmedizin; 2006. Finkbeiner WE. Physiology and pathology of tracheobronchial glands. Respir Physiol 1999;118: 77–83. van der Schans CP. Bronchial mucus transport. Respir Care 2007;52:1150–6. Nishino T, Hiraga K, Tadanobu M, et al. Respiratory reflex responses to stimulation of tracheal mucosa in enflurane-anesthetized humans. J Appl Phys 1988; 65:1069–74.
5