Anatomy, pathology, and physiology of the tracheobronchial tree: Emphasis on the distal airways
2009; Elsevier BV; Volume: 124; Issue: 6 Linguagem: Inglês
10.1016/j.jaci.2009.08.048
ISSN1097-6825
AutoresDallas M. Hyde, Qutayba Hamid, Charles G. Irvin,
Tópico(s)Neuroscience of respiration and sleep
ResumoThis article covers the airway tree with respect to anatomy, pathology, and physiology. The anatomic portion discusses various primate groups so as to help investigators understand similarities and differences between animal models. An emphasis is on distal airway findings. The pathology section focuses on the inflammatory responses that occur in proximal and distal airways. The physiologic review brings together the anatomic and pathologic components to the functional state and proposes ways to evaluate the small airways in patients with asthma. This article covers the airway tree with respect to anatomy, pathology, and physiology. The anatomic portion discusses various primate groups so as to help investigators understand similarities and differences between animal models. An emphasis is on distal airway findings. The pathology section focuses on the inflammatory responses that occur in proximal and distal airways. The physiologic review brings together the anatomic and pathologic components to the functional state and proposes ways to evaluate the small airways in patients with asthma. Anatomy of the tracheobronchial tree with emphasis on the distal airways: consequences of distal airway abnormalitiesThe tracheobronchial conducting airways form a complex series of branching tubes that culminate in the gas exchange area, with the average number of branches approximately the same for most mammalian species (Table I).1Plopper C. Hyde D.M. Epithelial cells of bronchioles.in: Parent R.A. Treatise on pulmonary toxicology: comparative biology of the normal lung. CRC Press, Boca Raton (FL)1992: 85-92Google Scholar, 2Mariassy A.T. Epithelial cells of trachea and bronchi.in: Parent R.A. Treatise on pulmonary toxicology: comparative biology of the normal lung. CRC Press, Boca Raton (FL)1992: 63-76Google Scholar, 3McBride J.T. Architecture of the tracheobronchial tree.in: Parent R.A. Treatise on pulmonary toxicology: comparative biology of the normal lung. CRC Press, Boca Raton (FL)1992: 49-61Google Scholar, 4Tyler W.S. Julian M.D. Gross and subgross anatomy of lungs, pleura, connective tissue septa, distal airways, and structural units.in: Parent R.A. Treatise on pulmonary toxicology: comparative biology of the normal lung. CRC Press, Boca Raton (FL)1992: 37-48Google Scholar The more proximal of these branches, the bronchi, are usually characterized by their unique histologic composition, including the presence of mucus and basal cells in the epithelium, mucosal glands in the interstitium, and a significant amount of cartilage in the interstitial spaces. More distally, the bronchioles have a thinner wall, the complex nature of the airway epithelial population is reduced, and the preponderance of the wall is composed of smooth muscle with little to no cartilage. The tracheobronchial airways occupy approximately 1%, 2%, or 11% of the lung volume in human subjects, rhesus monkeys, and rodents, respectively. The remainder of the lung is comprised of large vessels and parenchyma (small vessels and bronchioles, interalveolar septa, and alveolar airspaces). In human subjects and nonhuman primates, cartilage is found in the walls of the tracheobronchial airways, from the trachea distally to the smallest bronchioles. In the distal bronchioles of human subjects and rhesus monkeys, cartilage is restricted to a small zone in the bifurcation area. By contrast, cartilage ends at the lobar bronchus in mice and rats. All species have a significant number of generations of intrapulmonary airways that are very thin walled and with minimal cartilage (nonrespiratory bronchioles). The organization of the zone of transition between conducting airways and the gas exchange area separates the lungs of primates and carnivores from those of other mammalian species. In primates and carnivores there is an extensive transition zone, with the walls of the distal airways having a mixture of bronchiolar epithelial cells mixed among alveolar outpockets.Table IComparison of species differences in tracheobronchial airway organization1Plopper C. Hyde D.M. Epithelial cells of bronchioles.in: Parent R.A. Treatise on pulmonary toxicology: comparative biology of the normal lung. CRC Press, Boca Raton (FL)1992: 85-92Google Scholar, 2Mariassy A.T. Epithelial cells of trachea and bronchi.in: Parent R.A. Treatise on pulmonary toxicology: comparative biology of the normal lung. CRC Press, Boca Raton (FL)1992: 63-76Google Scholar, 3McBride J.T. Architecture of the tracheobronchial tree.in: Parent R.A. Treatise on pulmonary toxicology: comparative biology of the normal lung. CRC Press, Boca Raton (FL)1992: 49-61Google Scholar, 4Tyler W.S. Julian M.D. Gross and subgross anatomy of lungs, pleura, connective tissue septa, distal airways, and structural units.in: Parent R.A. Treatise on pulmonary toxicology: comparative biology of the normal lung. CRC Press, Boca Raton (FL)1992: 37-48Google ScholarParameterHumanMonkeyMouseLung %11.811Cartilage in wallTrachea to distal bronchioleTrachea to distal bronchioleTrachea to lobar bronchiNonrespiratory bronchioleSeveral generationsSeveral generationsSeveral generationsRespiratory bronchiolesSeveral generationsSeveral generationsNone or 1Generations to respiratory bronchiole (axial path)17-2113-1713-17Branching patternDichotomousDichotomous/trichotomousMonopodial Open table in a new tab The walls of tracheobronchial airways are highly complex cellular structures. All the airway wall compartments (epithelium and interstitium) making up the wall are present to varying degrees in all species. In all species the interstitium of the tracheal wall contains C-shaped cartilage, and there is a band of smooth muscle that joins the open end of the cartilage. The trachea and proximal airways have extensive submucosal glands beneath the epithelium in rhesus monkeys and human subjects. These glands are present to a variable extent in smaller laboratory species. There is a substantial difference among species in the amount of epithelium that lines the luminal surface in the trachea. The thickness of the epithelium in the trachea of rhesus monkeys is approximately twice that of mice and rats and one half to one third that of human subjects. Other major differences between species are the composition of the epithelium, the density of cells lining the surface, and the proportion of cell phenotypes in the epithelium. Mucus cells are a substantial percentage of the airway in primates but generally not to a substantial extent in the tracheas of healthy, pathogen-free mice and rats. The proportion of ciliated cells in the epithelium is relatively similar in all species, yet the proportion of basal cells found in the epithelial surface varies by species. As would be expected with the differences in secretory cell populations that line the trachea of different species, there is considerable variation in the carbohydrate content of the secretory product. Primates in general have a more heavily sulfated secretory product that is not usually found in laboratory mammals. The difference in secretory product composition is also reflected, to some degree, in the composition of the carbohydrates in tracheal submucosal glands.The organization of the tracheobronchial airways varies by airway generation within the airway tree. The largest, most proximal intrapulmonary bronchi show considerable organizational variation between species. Although smooth muscle is present in the walls of all mammalian species, there is a substantial difference in the extent of cartilage found in the lobar bronchus in laboratory mammals and in the distribution of submucosal glands. Epithelium is reduced in thickness in more distal airways compared with that seen in the trachea. There are also major differences in the organization of the surface epithelial population, with mucus and basal cells predominating in primates and Clara cells being the principal nonciliated cell population in other laboratory animals. In the most distal conducting airways, the bronchioles, the major differences between species are related primarily to the epithelial surface lining. In laboratory mammals the Clara cell is the primary secretory cell phenotype, and there are no mucous cells. The extent of basal cells in the epithelium varies by the extent of alveolarization. The bronchioles of rhesus monkeys have an extensive smooth muscle portion, which is arranged in large bundles and is interspersed with extensive connective tissue not generally observed in smaller laboratory mammals.Alterations of the distal airways in rhesus monkeys, including decreased diameter, smooth muscle hyperplasia and hypertrophy, inflammatory cell accumulation (CD4+ cells, IgE+ cells, dendritic cells, eosinophils, and mast cells), basement membrane thickening/thinning, mucous cell metaplasia, and increased airway production of cytokines (IL-4, IL-5, macrophage chemoattractant protein 3, IL-12p40, IL-17, and eotaxin 2 and 3) and growth factors (fibroblast growth factor 2; vascular endothelial growth factor 121, 165; and TGF-β), were observed after house dust mite and ozone inhalation.5Miller L.A. Hurst S.D. Coffman R.L. Tyler N.K. Stovall M.Y. Chou D.L. et al.Airway generation-specific differences in the spatial distribution of immune cells and cytokines in allergen-challenged rhesus monkeys.Clin Exp Allergy. 2005; 35: 894-906Crossref PubMed Scopus (37) Google Scholar, 6Chou D.L. Daugherty B.L. McKenna E.K. Hsu W.M. Tyler N.K. Plopper C.G. et al.Chronic aeroallergen during infancy enhances eotaxin-3 expression in airway epithelium and nerves.Am J Respir Cell Mol Biol. 2005; 33: 1-8Crossref PubMed Scopus (19) Google Scholar, 7Schelegle E.S. Miller L.A. Gershwin L.J. Fanucchi M.V. Van Winkle L.S. Gerriets J.E. et al.Repeated episodes of ozone inhalation amplifies the effects of allergen sensitization and inhalation on airway immune and structural development in Rhesus monkeys.Toxicol Appl Pharmacol. 2003; 191: 74-85Crossref PubMed Scopus (86) Google Scholar, 8Schelegle E.S. Gershwin L.J. Miller L.A. Fanucchi M.V. Van Winkle L.S. Gerriets J.P. et al.Allergic asthma induced in rhesus monkeys by house dust mite (Dermatophagoides farinae).Am J Pathol. 2001; 158: 333-341Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar The same changes are observed in the distal airways of human subjects with asthma.9Despas P.J. Leroux M. Macklem P.T. Site of airway obstruction in asthma as determined by measuring maximal expiratory flow breathing air and a helium-oxygen mixture.J Clin Invest. 1972; 51: 3235-3243Crossref PubMed Scopus (170) Google Scholar, 10Levine G. Housley E. MacLeod P. Macklem P.T. Gas exchange abnormalities in mild bronchitis and asymptomatic asthma.N Engl J Med. 1970; 282: 1277-1282Crossref PubMed Scopus (66) Google Scholar, 11Carroll N. Cooke C. James A. The distribution of eosinophils and lymphocytes in the large and small airways of asthmatics.Eur Respir J. 1997; 10: 292-300Crossref PubMed Scopus (229) Google Scholar, 12Faul J.L. Tormey V.J. Leonard C. Burke C.M. Farmer J. Horne S.J. et al.Lung immunopathology in cases of sudden asthma death.Eur Respir J. 1997; 10: 301-307Crossref PubMed Scopus (113) Google Scholar, 13Hamid Q. Song Y. Kotsimbos T.C. Minshall E. Bai T.R. Hegele R.G. et al.Inflammation of small airways in asthma.J Allergy Clin Immunol. 1997; 100: 44-51Abstract Full Text Full Text PDF PubMed Scopus (491) Google ScholarHistologic examples of proximal to distal airways are shown in Fig 1.Pathology of distal airways in patients with asthmaPathologic evidence has emerged in the last few years suggesting that the airway inflammation and remodeling that characterize asthma occur not only in the central airways but extend to the distal lung and the lung parenchyma. The correlation between pathologic features and physiologic responses has been suggested by many studies. However, it is still unclear whether treating the inflammation in the distal airways is associated with better control of asthma and whether deposition of anti-inflammatory drugs to the distal region of the lung can lead to the prevention of remodeling in this area.Pathology of the large and small airwaysAsthma is characterized by inflammatory cell infiltration into the airways, an upregulation of TH2 cytokines, and structural changes, including epithelial detachment, subepithelial fibrosis, and increased smooth muscle mass. The majority of these observations have been obtained from studies that sampled central airways because bronchoscopic sampling was largely limited to proximal airway sites. A role of the distal airways and lung parenchyma in patients with asthma has been suggested by studies conducted in the early 1970s.9Despas P.J. Leroux M. Macklem P.T. Site of airway obstruction in asthma as determined by measuring maximal expiratory flow breathing air and a helium-oxygen mixture.J Clin Invest. 1972; 51: 3235-3243Crossref PubMed Scopus (170) Google Scholar, 10Levine G. Housley E. MacLeod P. Macklem P.T. Gas exchange abnormalities in mild bronchitis and asymptomatic asthma.N Engl J Med. 1970; 282: 1277-1282Crossref PubMed Scopus (66) Google Scholar However, investigation of the pathology of the distal airways lagged because of the difficulties in obtaining adequate tissue from the peripheral structures.Early studies looking at the pathology of distal airway disease originated from autopsy specimens11Carroll N. Cooke C. James A. The distribution of eosinophils and lymphocytes in the large and small airways of asthmatics.Eur Respir J. 1997; 10: 292-300Crossref PubMed Scopus (229) Google Scholar, 12Faul J.L. Tormey V.J. Leonard C. Burke C.M. Farmer J. Horne S.J. et al.Lung immunopathology in cases of sudden asthma death.Eur Respir J. 1997; 10: 301-307Crossref PubMed Scopus (113) Google Scholar and have demonstrated that the entire length of the airway is involved in asthma. Carroll et al12Faul J.L. Tormey V.J. Leonard C. Burke C.M. Farmer J. Horne S.J. et al.Lung immunopathology in cases of sudden asthma death.Eur Respir J. 1997; 10: 301-307Crossref PubMed Scopus (113) Google Scholar have examined the distribution of inflammatory cells throughout the bronchial trees of patients who experienced both fatal and nonfatal asthma and have shown increased numbers of lymphocytes and eosinophils to be uniformly distributed throughout the large and distal airways of both patients with mild and those with severe asthma when compared with those seen in control subjects. Similarly, Hamid et al13Hamid Q. Song Y. Kotsimbos T.C. Minshall E. Bai T.R. Hegele R.G. et al.Inflammation of small airways in asthma.J Allergy Clin Immunol. 1997; 100: 44-51Abstract Full Text Full Text PDF PubMed Scopus (491) Google Scholar have demonstrated, using resected lung specimens from asthmatic and nonasthmatic patients, that the inflammatory response in asthma is not restricted to the proximal airways. They reported increased numbers of T cells (CD3 cells), total eosinophils (major basic protein–staining cells), and activated eosinophils (EG2+ cells) in both the large and distal airways of asthmatic patients when compared with those seen in control subjects. Comparing the large and distal airways directly, a greater number of activated eosinophils (EG2) was seen in airways with an internal diameter of less than 2 mm compared with larger airways. In these patients Minshall et al14Minshall E.M. Hogg J.C. Hamid Q.A. Cytokine mRNA expression in asthma is not restricted to the large airways.J Allergy Clin Immunol. 1998; 101: 386-390Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar have also shown increased numbers of IL-5 and IL-4 mRNA–positive cells in the distal airways of asthmatic patients compared with those seen in nonasthmatic control subjects, and more importantly, the expression of IL-5 mRNA was increased in the distal airways compared with that seen in the large airways.14Minshall E.M. Hogg J.C. Hamid Q.A. Cytokine mRNA expression in asthma is not restricted to the large airways.J Allergy Clin Immunol. 1998; 101: 386-390Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar The increased expression of eotaxin and monocyte chemotactic protein 4 mRNA also has been reported to be present in the epithelial cell layer and in the airway wall of the distal airways of asthmatic patients compared with that seen in nonasthmatic control subjects.15Taha R.A. Minshall E.M. Miotto D. Shimbara A. Luster A. Hogg J.C. et al.Eotaxin and monocyte chemotactic protein-4 mRNA expression in small airways of asthmatic and nonasthmatic individuals.J Allergy Clin Immunol. 1999; 103: 476-483Abstract Full Text Full Text PDF PubMed Google Scholar In this study the number of chemokine-positive cells in the distal airways correlated with the number of major basic protein–positive eosinophils at the same site. Chemokines were also demonstrated in the smooth muscle of the distal airways, and inflammation was detected outside the smooth muscle area. These observations have been confirmed by Haley et al,16Haley K.J. Sunday M.E. Wiggs B.R. Kozakewich H.P. Reilly J.J. Mentzer S.J. et al.Inflammatory cell distribution within and along asthmatic airways.Am J Respir Crit Care Med. 1998; 158: 565-572Crossref PubMed Scopus (144) Google Scholar who showed that inflammation extends beyond the airway smooth muscle of the distal lung in patients who died of asthma and suggested a significant role of this inflammation to the pathophysiology of asthma.Using endobronchial and transbronchial biopsies, Kraft et al17Kraft M. Djukanovic R. Wilson S. Holgate S.T. Martin R.J. Alveolar tissue inflammation in asthma.Am J Respir Crit Care Med. 1996; 154: 1505-1510Crossref PubMed Scopus (507) Google Scholar, 18Kraft M. Martin R.J. Wilson S. Djukanovic R. Holgate S.T. Lymphocyte and eosinophil influx into alveolar tissue in nocturnal asthma.Am J Respir Crit Care Med. 1999; 159: 228-234Crossref PubMed Scopus (186) Google Scholar have shown alveolar inflammation in patients with nocturnal asthma (NA), which is not present in those with nonnocturnal asthma (NNA). Patients with NA had increased numbers of eosinophils per lung volume in their lung parenchyma at 4 am compared with patients without NA, and the patients with NA had a greater number of eosinophils and macrophages in their alveolar tissue at 4 am than at 4 pm. In addition, in the patients with NA, only alveolar (and not central airway) eosinophilia correlated with an overnight reduction in lung function. Those same investigators have shown increased numbers of CD4 cells in the alveolar tissue of patients with NA at 4 am compared with those found in patients with NNA. Although the number of CD4 cells in the endobronchial lamina propria was higher than that in the alveolar tissue, once again, only the alveolar tissue CD4 lymphocytes correlated with the predicted lung function (ie, FEV1) at 4 am (r = 0.68) and with the number of activated alveolar eosinophils (r = 0.66). In this same patient cohort, NA was associated with reduced glucocorticoid receptor (GR)–binding affinity, reduced proliferation of blood mononuclear cells, and decreased responsiveness to steroids at 4 am compared with that seen in patients with NNA.19Kraft M. Vianna E. Martin R.J. Leung D.Y. Nocturnal asthma is associated with reduced glucocorticoid receptor binding affinity and decreased steroid responsiveness at night.J Allergy Clin Immunol. 1999; 103: 66-71Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar These findings have suggested that the increased numbers of CD4 cells in the alveolar tissue of patients with NA, the reduced GR-binding affinity, and the reduced steroid responsiveness might be responsible for promoting eosinophil influx and exacerbations of symptoms in patients with NA. One of the mechanisms that might be responsible for this phenomenon is an upregulation of GRβ, which has been reported previously20Christodoulopoulos P. Leung D.Y. Elliott M.W. Hogg J.C. Muro S. Toda M. et al.Increased number of glucocorticoid receptor-beta-expressing cells in the airways in fatal asthma.J Allergy Clin Immunol. 2000; 106: 479-484Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar in the peripheral airways of steroid-insensitive subjects with severe asthma. The main cells expressing GRβ are CD3 T lymphocytes and, to a lesser extent, eosinophils, neutrophils, and macrophages. These results suggested that the increased number of GRβ+ cells in the distal airways of patients with fatal asthma might be associated with steroid resistance, contributing to asthma mortality.Similar distal airway inflammation has been reported in symptomatic, steroid-dependent asthmatic patients with severe disease. Using endobronchial and transbronchial biopsies, Wenzel et al21Wenzel S.E. Szefler S.J. Leung D.Y. Sloan S.I. Rex M.D. Martin R.J. Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids.Am J Respir Crit Care Med. 1997; 156: 737-743Crossref PubMed Scopus (696) Google Scholar reported persistent proximal and distal airway inflammation. Although the number of eosinophils was similar between patients with severe asthma and healthy control subjects, asthmatic patients with severe disease had high numbers and percentages of neutrophils in their bronchoalveolar lavage fluid and endobronchial and transbronchial biopsy specimens when compared with asthmatic patients with mild-to-moderate disease, despite receiving aggressive treatment with steroids. It has been speculated that the inflammatory cell density in the distal airways in patients with severe asthma might relate to the peripheral airway obstruction that is characteristic of this disease. The distal airway inflammation might cause an uncoupling of the parenchyma and airways because of the mechanical interdependence between these 2 compartments, leading to changes in the overall accumulated lung mechanics in asthmatic patients. Recently, evidence has been accumulated in the central22Al-Ramli W. Prefontaine D. Chouiali F. Martin J.G. Olivenstein R. Lemiere C. et al.T(H)17-associated cytokines (IL-17A and IL-17F) in severe asthma.J Allergy Clin Immunol. 2009; 123: 1185-1187Abstract Full Text Full Text PDF PubMed Scopus (469) Google Scholar and peripheral (unpublished data) airways of patients with severe asthma that another subset of T cells is present (TH17 cells). This might explain the steroid hyporesponsiveness and neutrophilia seen in this subtype of the disease.The nature of airway wall remodeling has been reasonably well described in the large airways; however, relatively little is known about structural remodeling of the distal airways. Subepithelial fibrosis and thickening have been reported as a result of excess deposition of collagen, laminin, fibronectin, and proteoglycans in the airway walls of asthmatic patients, and changes in these structural proteins have been positively correlated with airway responsiveness to methacholine. In a modeling study, Wiggs et al23Wiggs B.R. Bosken C. Pare P.D. James A. Hogg J.C. A model of airway narrowing in asthma and in chronic obstructive pulmonary disease.Am Rev Respir Dis. 1992; 145: 1251-1258Crossref PubMed Scopus (391) Google Scholar have shown that a moderate increase in distal airway wall thickness, which has little effect on baseline resistance, can profoundly affect the airway narrowing caused by airway smooth muscle shortening. The combination of peripheral airway wall thickening and a loss of lung recoil are additive in their effect on enhanced airway responsiveness. In that study the investigators concluded that the contribution of the distal airways to total lung resistance has been thus far grossly underestimated and that the physiologic outcome is largely dependent on the frequency used to measure the peripheral lung mechanics. Bergeron et al24Bergeron C. Hauber H.P. Gotfried M. Newman K. Dhanda R. Servi R.J. et al.Evidence of remodeling in peripheral airways of patients with mild to moderate asthma: effect of hydrofluoroalkane-flunisolide.J Allergy Clin Immunol. 2005; 116: 983-989Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar have demonstrated a considerable amount of subepithelial fibrosis and increase in smooth muscle mass in the distal airways of asthmatic patients but could not find any evidence of epithelial detachment. They have also shown that smooth muscle mass in the distal airways could be reduced in response to treatment.ConclusionA large body of literature has suggested that airway inflammation occurs throughout the airway. Although the clinical significance of the distal airways and the lung parenchyma in asthma is not yet known, it is possible that poorly controlled inflammation in peripheral airways, which are not reached by conventional inhaled steroids, might contribute to an accelerated decrease in lung function and airway remodeling.Physiology of the tracheobronchial tree and physiologic techniques to evaluate the distal lungIn 1967, Malcolm Green25Green M. How big are the bronchioles? St Thomas. Hospital Gazette 1964;62:136-9.Google Scholar wrote a provocative essay that debunked the then commonly held notion that most of the resistance to airflow was attributed to the smallest airways.26Nadel J.A. Colebatch J.H. Olsen C.R. Location and mechanism of airway constriction after barium sulfate microembolism.J Appl Physiol. 1964; 19: 387-394PubMed Google Scholar, 27D'Silva J.L. Lewis A.F. The measurement of bronchoconstriction in vivo.J Physiol. 1961; 157: 611-622PubMed Google Scholar Using the recently published morphometric measurements of Weibel for airway size, length, and number28Weibel E.R. Morphometry of the human lung. Academic Press, New York1963Crossref Google Scholar and the simple laminar flow equation, Green's model suggested that the major source of resistance to breathing was in the central or large airways and not the smaller airways. Moreover, airways less than 2 mm in diameter or beyond 13 generations of airway branching contributed virtually nothing to total resistance. Two years later, Macklem and Mead29Macklem P.T. Mead J. Resistance of central and peripheral airways measured by a retrograde catheter.J Appl Physiol. 1967; 22: 395-401PubMed Google Scholar proved that Green's predictions were correct with direct measurements of small (<2 mm) airway resistance using the retrograde catheter. Hogg et al30Hogg J.C. Macklem P.T. Thurlbeck W.M. Site and nature of airway obstruction in chronic obstructive lung disease.N Engl J Med. 1968; 278: 1355-1360Crossref PubMed Scopus (979) Google Scholar then showed the same was true for the airways of human subjects. Both of these studies demonstrated that small ( 2 mm] vs small [<2 mm]).The large conducting airways have several important mechanisms that alter airway patency. These include neural influences (parasympathetic, nonadrenergic, and adrenergic), structural support (eg, cartilage), smooth muscle tone, and, perhaps most importantly, the profound effects of lung volume.32Irvin C.G. Lung volume: a principle determinant of airway smooth muscle function.Eur Respir J. 2003; 22: 3-5Crossref PubMed Scopus (16) Google Scholar On the other hand, we know that small airways have almost none of these protective mechanisms; nerves generally do not penetrate that deep into the small airways, small airways do not have cartilaginous support, and surfactant is important to their patency.33Macklem P.T. Proctor D.F. Hogg J.C. The stability of peripheral airways.Respir Physiol. 1970; 8: 191-203Crossref PubMed Scopus (208) Google Scholar Smooth muscle does exist in smaller airways, but without parenchymal airway independence, the activation of small-airway smooth muscle leads to uninhibited small-airway narrowing.34Macklem P.T. The physiology of small airways.Am J Respir Crit Care Med. 1998; 157: S181-S183Crossref PubMed Scopus (174) Google Scholar As was shown years ago, the ability to increase airway diameter as a function of increasing lung volume is not a feature of airways less than 2 mm in diameter.29Macklem P.T. Mead J. Resistance of central and peripheral airways measured by a retrograde catheter.J Appl Physiol. 1967; 22: 395-401PubMed Google Scholar, 30Hogg J.C. Macklem P.T. Thurlbeck W.M. Site and nature of airway obstruction in chronic obstructive lung disease.N Engl J Med. 1968; 278: 1355-1360Crossref PubMed Scopus (979) Google Scholar It has been calculated and supported by experimental evidence that airway resistance could increase 10-fold without a significant increase in overall pulmonary resistance because these airways contribute minimally to total resistance.29Macklem P.T. Mead J. Resistance of central and peripheral airways measured by a retrograde catheter.J Appl Physiol. 1967; 22: 395-401PubMed Google Scholar, 30Hogg J.C. Macklem P.T. Thurlbeck W.M. Site and nature of airway obstruction in chronic obstructive lung disease.N Engl J Med. 1968; 278: 1355-1360Crossref PubMed Scopus (979) Google Scholar, 31Mead J. The lung's “quiet zone.”.N Engl J Med. 1970; 282: 1318-1319Crossref PubMed Scopus (175) Google Scholar Because there are estimated to be 24,000 small airways and bronchioles,28Weibel E.R. Morphometry of the human lung. Academic Press, New York1963Crossref Google Scholar thousands could be narrowed or totally obstructed without a significant loss
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