Exploring Histologic Emphysema in a Rural Lobectomy Cohort: Insights and a Review Correlations of Histologic Emphysema

Main Article Content

Rahul G. Sangani, MD http://orcid.org/0000-0002-6459-1298 Vishal Deepak Bhanusowmya Buragamadagu Andrew J. Ghio


Exposure to cigarette smoking is extensive in rural Appalachia where one in four adults’ smokes. The clinical implications of this habit are evident among patients with some of the highest national rates for chronic obstructive pulmonary disease (COPD), lung cancer, and pulmonary fibrosis. Individuals undergoing surgical lung resection for suspicious lung nodules or masses at a major rural academic center in the area demonstrated an excessive burden of histologic emphysema (73.5%). This destructive process of the alveoli was linked to a significant burden of comorbid conditions, various radiologic patterns of interstitial lung diseases and interstitial lung abnormalities, histologic fibrosis, inflammatory processes (respiratory bronchitis, desquamative interstitial pneumonia, peribronchiolar metaplasia), anthracosis, and lung cancer. Physiologically, this combination of injuries imposed substantial limitations. Findings presented may enhance the understanding of concurrent changes occurring in the smoker. The complex inter-relationships and disparities between clinical COPD, radiologic and histologic emphysema are defined. While emphysema remains an irreversible pathology, associated inflammatory and fibrotic conditions are possibly amenable to earlier smoking cessation strategies and available disease-modifying therapies.

Keywords: Cigarette Smoking, Emphysema, Fibrosis, Histology, Radiology, Smoking Cessation

Article Details

How to Cite
SANGANI, Rahul G. et al. Exploring Histologic Emphysema in a Rural Lobectomy Cohort: Insights and a Review. Medical Research Archives, [S.l.], v. 12, n. 4, apr. 2024. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/5265>. Date accessed: 27 may 2024. doi: https://doi.org/10.18103/mra.v12i4.5265.
Review Articles


1. Thurlbeck WM, Muller NL. Emphysema: definition, imaging, and quantification. AJR Am J Roentgenol. Nov 1994;163(5):1017-25. doi:10.2214/ajr.163.5.7976869

2. Beghe B, Cerri S, Fabbri LM, Marchioni A. COPD, Pulmonary Fibrosis and ILAs in Aging Smokers: The Paradox of Striking Different Responses to the Major Risk Factors. Int J Mol Sci. Aug 27 2021;22(17)doi:10.3390/ijms22179292

3. Ridge CA, McErlean AM, Ginsberg MS. Epidemiology of lung cancer. Semin Intervent Radiol. Jun 2013;30(2):93-8. doi:10.1055/s-0033-1342949

4. Sangani RG, Deepak V, Anwar J, Patel Z, Ghio AJ. Cigarette Smoking, and Blood Monocyte Count Correlate with Chronic Lung Injuries and Mortality. Int J Chron Obstruct Pulmon Dis. 2023;18:431-446. doi:10.2147/C OPD.S397667

5. Sangani RG, Deepak V, Ghio AJ, et al. Interstitial lung abnormalities and interstitial lung diseases associated with cigarette smoking in a rural cohort undergoing surgical resection. BMC Pulm Med. Apr 29 2022;22(1): 172. doi:10.1186/s12890-022-01961-9

6. Vij N, Chandramani-Shivalingappa P, Van Westphal C, Hole R, Bodas M. Cigarette smoke-induced autophagy impairment accelerates lung aging, COPD-emphysema exacerbations and pathogenesis. Am J Physiol Cell Physiol. Jan 1 2018;314(1):C73-C87. doi:10.1152/ajpcell.00110.2016

7. Tobacco Use in West Virginia (2022).

8. Cardarelli K, Westneat S, Dunfee M, May B, Schoenberg N, Browning S. Persistent disparities in smoking among rural Appalachians: evidence from the Mountain Air Project. BMC Public Health. Feb 2 2021;21 (1):270. doi:10.1186/s12889-021-10334-6

9. Croft JB, Wheaton AG, Liu Y, et al. Urban-Rural County and State Differences in Chronic Obstructive Pulmonary Disease - United States, 2015. MMWR Morb Mortal Wkly Rep. Feb 23 2018;67(7):205-211. doi:10.15585/m mwr.mm6707a1

10. Auerbach O, Hammond EC, Garfinkel L, Benante C. Relation of smoking and age to emphysema. Whole-lung section study. N Engl J Med. Apr 20 1972;286(16):853-7. doi: 10.1056/NEJM197204202861601

11. Bhatt SP, Kim YI, Harrington KF, et al. Smoking duration alone provides stronger risk estimates of chronic obstructive pulmonary disease than pack-years. Thorax. May 2018;73 (5):414-421. doi:10.1136/thoraxjnl-2017-210722

12. Pleasants RA, Rivera MP, Tilley SL, Bhatt SP. Both Duration and Pack-Years of Tobacco Smoking Should Be Used for Clinical Practice and Research. Ann Am Thorac Soc. Jul 2020;17(7):804-806. doi:10.1513/AnnalsATS.202002-133VP

13. Jagoe RT, Engelen MP. Muscle wasting and changes in muscle protein metabolism in chronic obstructive pulmonary disease. Eur Respir J Suppl. Nov 2003;46:52s-63s. doi:10.1 183/09031936.03.00004608

14. Casanova C, de Torres JP, Aguirre-Jaime A, et al. The progression of chronic obstructive pulmonary disease is heterogeneous: the experience of the BODE cohort. Am J Respir Crit Care Med. Nov 1 2011;184(9):1015-21. doi:10.1164/rccm.201105-0831OC

15. Celli BR, Locantore N, Tal-Singer R, et al. Emphysema and extrapulmonary tissue loss in COPD: a multi-organ loss of tissue phenotype. Eur Respir J. Feb 2018;51(2)doi:1 0.1183/13993003.02146-2017

16. Shaikh M, Sood RG, Sarkar M, Thakur V. Quantitative Computed Tomography (CT) Assessment of Emphysema in Patients with Severe Chronic Obstructive Pulmonary Disease (COPD) and its Correlation with Age, Sex, Pulmonary Function Tests, BMI, Smoking, and Biomass Exposure. Pol J Radiol. 2017;82:760-766. doi:10.12659/PJR.903278

17. Health Disparities in Appalachia (2017).

18. Chatila WM, Thomashow BM, Minai OA, Criner GJ, Make BJ. Comorbidities in chronic obstructive pulmonary disease. Proc Am Thorac Soc. May 1 2008;5(4):549-55. doi:10.1 513/pats.200709-148ET

19. Almagro P, Cabrera FJ, Diez J, et al. Comorbidities and short-term prognosis in patients hospitalized for acute exacerbation of COPD: the EPOC en Servicios de medicina interna (ESMI) study. Chest. Nov 2012;142(5): 1126-1133. doi:10.1378/chest.11-2413

20. Baty F, Putora PM, Isenring B, Blum T, Brutsche M. Comorbidities and burden of COPD: a population based case-control study. PLoS One. 2013;8(5):e63285. doi:10.13 71/journal.pone.0063285

21. Lin PJ, Shaya FT, Scharf SM. Economic implications of comorbid conditions among Medicaid beneficiaries with COPD. Respir Med. May 2010;104(5):697-704. doi:10.1016/j .rmed.2009.11.009

22. Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects. 1986.

23. Guilliams M, Mildner A, Yona S. Developmental and Functional Heterogeneity of Monocytes. Immunity. Oct 16 2018;49(4):5 95-613. doi:10.1016/j.immuni.2018.10.005

24. Lugg ST, Scott A, Parekh D, Naidu B, Thickett DR. Cigarette smoke exposure and alveolar macrophages: mechanisms for lung disease. Thorax. Jan 2022;77(1):94-101. doi:1 0.1136/thoraxjnl-2020-216296

25. Cornwell WD, Kim V, Fan X, et al. Activation and polarization of circulating monocytes in severe chronic obstructive pulmonary disease. BMC Pulm Med. Jun 15 2018;18(1):101. doi:10.1186/s12890-018-0664-y

26. van de Laar L, Saelens W, De Prijck S, et al. Yolk Sac Macrophages, Fetal Liver, and Adult Monocytes Can Colonize an Empty Niche and Develop into Functional Tissue-Resident Macrophages. Immunity. Apr 19 2016;44(4):755-68. doi:10.1016/j.immuni.2016.02.017

27. Yona S, Kim KW, Wolf Y, et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity. Jan 24 2013;38(1):79-91. doi:10.1016/j.immuni.2012.12.001

28. Guilliams M, De Kleer I, Henri S, et al. Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF. J Exp Med. Sep 23 2013;210(10):1977-92. doi:10.10 84/jem.20131199

29. Byrne AJ, Powell JE, O'Sullivan BJ, et al. Dynamics of human monocytes and airway macrophages during healthy aging and after transplant. J Exp Med. Mar 2 2020;217(3)doi:1 0.1084/jem.20191236

30. Gibbings SL, Goyal R, Desch AN, et al. Transcriptome analysis highlights the conserved difference between embryonic and postnatal-derived alveolar macrophages. Blood. Sep 10 2015;126(11):1357-66. doi:10. 1182/blood-2015-01-624809

31. Misharin AV, Morales-Nebreda L, Reyfman PA, et al. Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J Exp Med. Aug 7 2017;214(8):2387-2404. doi:10.1084/jem.20162152

32. Fingerle G, Pforte A, Passlick B, Blumenstein M, Strobel M, Ziegler-Heitbrock HW. The novel subset of CD14+/CD16+ blood monocytes is expanded in sepsis patients. Blood. Nov 15 1993;82(10):3170-6.

33. Nockher WA, Scherberich JE. Expanded CD14+ CD16+ monocyte subpopulation in patients with acute and chronic infections undergoing hemodialysis. Infect Immun. Jun 1998;66(6):2782-90. doi:10.1128/IAI.66.6.2782-2790.1998

34. Ziegler-Heitbrock L. Blood Monocytes and Their Subsets: Established Features and Open Questions. Front Immunol. 2015;6:423. doi:10.3389/fimmu.2015.00423

35. Auffray C, Sieweke MH, Geissmann F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol. 2009;27:669-92. doi:10.1146/annur ev.immunol.021908.132557

36. Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity. Jul 2003;19(1):71-82. doi:10.1016/s1074-761 3(03)00174-2

37. Hoogsteden HC, van Dongen JJ, van Hal PT, Delahaye M, Hop W, Hilvering C. Phenotype of blood monocytes and alveolar macrophages in interstitial lung disease. Chest. Mar 1989;95(3):574-7. doi:10.1378/ch est.95.3.574

38. Tacke F, Randolph GJ. Migratory fate and differentiation of blood monocyte subsets. Immunobiology. 2006;211(6-8):609-18. doi:1 0.1016/j.imbio.2006.05.025

39. Barnes PJ. Similarities and differences in inflammatory mechanisms of asthma and COPD. Breathe. March 1, 2011 2011;7(3):229-238. doi:https://doi.org/10.1183/20734735.026410

40. Kapellos TS, Bonaguro L, Gemund I, et al. Human Monocyte Subsets and Phenotypes in Major Chronic Inflammatory Diseases. Front Immunol. 2019;10:2035. doi:10.3389/fimmu. 2019.02035

41. Lin CH, Li YR, Lin PR, et al. Blood monocyte levels predict the risk of acute exacerbations of chronic obstructive pulmonary disease: a retrospective case-control study. Sci Rep. Dec 6 2022;12(1):2105 7. doi:10.1038/s41598-022-25520-8

42. Pedersen KM, Colak Y, Ellervik C, Hasselbalch HC, Bojesen SE, Nordestgaard BG. Smoking and Increased White and Red Blood Cells. Arterioscler Thromb Vasc Biol. May 2019;39(5):965-977. doi:10.1161/ATVBA HA.118.312338

43. Hai Y, Chen N, Wu W, et al. High postoperative monocyte indicates inferior Clinicopathological characteristics and worse prognosis in lung adenocarcinoma or squamous cell carcinoma after lobectomy. BMC Cancer. Oct 22 2018;18(1):1011. doi:10. 1186/s12885-018-4909-1

44. Hlapcic I, Dugac AV, Popovic-Grle S, et al. Influence of disease severity, smoking status and therapy regimes on leukocyte subsets and their ratios in stable chronic obstructive pulmonary disease. Arch Med Sci. 2022;18(3):672-681. doi:10.5114/aoms.2020.100720

45. Min B, Grant-Orser A, Johannson KA. Peripheral blood monocyte count and outcomes in patients with interstitial lung disease: a systematic review and meta-analysis. Eur Respir Rev. Sep 30 2023;32(169) doi:10.1183/16000617.0072-2023

46. Kreuter M, Lee JS, Tzouvelekis A, et al. Monocyte Count as a Prognostic Biomarker in Patients with Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. Jul 1 2021;204(1): 74-81. doi:10.1164/rccm.202003-0669OC

47. Scott MKD, Quinn K, Li Q, et al. Increased monocyte count as a cellular biomarker for poor outcomes in fibrotic diseases: a retrospective, multicentre cohort study. Lancet Respir Med. Jun 2019;7(6):497-508. doi:10.1016/S2213-2600(18)30508-3

48. Gurney JW, Jones KK, Robbins RA, et al. Regional distribution of emphysema: correlation of high-resolution CT with pulmonary function tests in unselected smokers. Radiology. May 1992;183(2):457-63. doi:10.1148/radiology.183.2.1561350

49. Li K, Gao Y, Pan Z, et al. Influence of Emphysema and Air Trapping Heterogeneity on Pulmonary Function in Patients with COPD. Int J Chron Obstruct Pulmon Dis. 2019;14:286 3-2872. doi:10.2147/COPD.S221684

50. Ferguson GT. Why does the lung hyperinflate? Proc Am Thorac Soc. Apr 2006;3 (2):176-9. doi:10.1513/pats.200508-094DO

51. McDonough JE, Yuan R, Suzuki M, et al. Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N Engl J Med. Oct 27 2011;365(17):1567-75. doi:10.1056/NEJMoa1106955

52. Lutchmedial SM, Creed WG, Moore AJ, Walsh RR, Gentchos GE, Kaminsky DA. How Common Is Airflow Limitation in Patients With Emphysema on CT Scan of the Chest? Chest. Jul 2015;148(1):176-184. doi:10.1378/chest. 14-1556

53. Kahnert K, Jobst B, Biertz F, et al. Relationship of spirometric, body plethysmographic, and diffusing capacity parameters to emphysema scores derived from CT scans. Chron Respir Dis. Jan-Dec 2019;16:1479972318775423. doi:10.1177/1479972318775423

54. Kellerer C, Jorres RA, Schneider A, et al. Prediction of lung emphysema in COPD by spirometry and clinical symptoms: results from COSYCONET. Respir Res. Sep 9 2021;22(1):2 42. doi:10.1186/s12931-021-01837-2

55. Cheng T, Li Y, Pang S, et al. Emphysema extent on computed tomography is a highly specific index in diagnosing persistent airflow limitation: a real-world study in China. Int J Chron Obstruct Pulmon Dis. 2019;14:13-26. doi:10.2147/COPD.S157141

56. de Weger WW, Klooster K, Ten Hacken NH, van Dijk M, Hartman JE, Slebos DJ. Determining Static Hyperinflation in Patients with Severe Emphysema: Relation Between Lung Function Parameters and Patient-Related Outcomes. Lung. Aug 2020;198(4):62 9-636. doi:10.1007/s00408-020-00368-9

57. Yoshikawa A, Sato S, Tanaka T, et al. Breakdown of lung framework and an increase in pores of Kohn as initial events of emphysema and a cause of reduction in diffusing capacity. Int J Chron Obstruct Pulmon Dis. 2016;11:2287-2294. doi:10.2147 /COPD.S114281

58. Diez Herranz A. RV/TLC% ratio: alternative criteria of normality. Eur Respir J. Oct 1995;8(10):1812-3. doi:10.1183/0903193 6.95.08101812

59. Cooper CB. The connection between chronic obstructive pulmonary disease symptoms and hyperinflation and its impact on exercise and function. Am J Med. Oct 2006;119(10 Suppl 1):21-31. doi:10.1016/j.am jmed.2006.08.004

60. Garcia-Rio F, Lores V, Mediano O, et al. Daily physical activity in patients with chronic obstructive pulmonary disease is mainly associated with dynamic hyperinflation. Am J Respir Crit Care Med. Sep 15 2009;180(6):506 -12. doi:10.1164/rccm.200812-1873OC

61. Kim YW, Lee CH, Hwang HG, et al. Resting hyperinflation and emphysema on the clinical course of COPD. Sci Rep. Mar 6 2019; 9(1):3764. doi:10.1038/s41598-019-40411-1

62. Diaz AA, Pinto-Plata V, Hernandez C, et al. Emphysema and DLCO predict a clinically important difference for 6MWD decline in COPD. Respir Med. Jul 2015;109(7):882-9. doi:10.1016/j.rmed.2015.04.009

63. Shiraishi Y, Tanabe N, Shimizu K, et al. Stronger Associations of Centrilobular Than Paraseptal Emphysema With Longitudinal Changes in Diffusing Capacity and Mortality in COPD. Chest. Aug 2023;164(2):327-338. doi: 10.1016/j.chest.2023.01.034

64. Balasubramanian A, Putcha N, MacIntyre NR, et al. Diffusing Capacity and Mortality in Chronic Obstructive Pulmonary Disease. Ann Am Thorac Soc. Jan 2023;20(1):38-46. doi:10. 1513/AnnalsATS.202203-226OC

65. de-Torres JP, O'Donnell DE, Marin JM, et al. Clinical and Prognostic Impact of Low Diffusing Capacity for Carbon Monoxide Values in Patients With Global Initiative for Obstructive Lung Disease I COPD. Chest. Sep 2021;160(3):872-878. doi:10.1016/j.chest.2021.04.033

66. Hata A, Schiebler ML, Lynch DA, Hatabu H. Interstitial Lung Abnormalities: State of the Art. Radiology. Oct 2021;301(1):19-34. doi:10 .1148/radiol.2021204367

67. Hatabu H, Hunninghake GM, Richeldi L, et al. Interstitial lung abnormalities detected incidentally on CT: a Position Paper from the Fleischner Society. Lancet Respir Med. Jul 2020;8(7):726-737. doi:10.1016/S2213-2600( 20)30168-5

68. Araki T, Nishino M, Zazueta OE, et al. Paraseptal emphysema: Prevalence and distribution on CT and association with interstitial lung abnormalities. Eur J Radiol. Jul 2015;84(7):1413-8. doi:10.1016/j.ejrad.2015.03.010

69. Washko GR, Hunninghake GM, Fernandez IE, et al. Lung volumes and emphysema in smokers with interstitial lung abnormalities. N Engl J Med. Mar 10 2011;364(10):897-906. doi:10.1056/NEJMoa1007285

70. Butler MW, Fabre A, Dodd JD. Smokers with interstitial lung abnormalities. N Engl J Med. Jun 23 2011;364(25):2465; author reply 2466. doi:10.1056/NEJMc1104014

71. King TE, Jr. Smoking and subclinical interstitial lung disease. N Engl J Med. Mar 10 2011;364(10):968-70. doi:10.1056/NEJMe1013966

72. Lee TS, Jin KN, Lee HW, et al. Interstitial Lung Abnormalities and the Clinical Course in Patients With COPD. Chest. Jan 2021;159(1):1 28-137. doi:10.1016/j.chest.2020.08.017

73. Liu Y, Tang J, Sun Y. Impact of Interstitial Lung Abnormalities on Disease Expression and Outcomes in COPD or Emphysema: A Systematic Review. Int J Chron Obstruct Pulmon Dis. 2023;18:189-206. doi:10.2147/C OPD.S392349

74. Ohgiya M, Matsui H, Tamura A, Kato T, Akagawa S, Ohta K. The Evaluation of Interstitial Abnormalities in Group B of the 2011 Global Initiative for Chronic Obstructive Lung Disease (GOLD) Classification of Chronic Obstructive Pulmonary Disease (COPD). Intern Med. Oct 15 2017;56(20):2711-2717. doi:10.2169/internalmedicine.8406-16

75. Otani H, Tanaka T, Murata K, et al. Smoking-related interstitial fibrosis combined with pulmonary emphysema: computed tomography-pathologic correlative study using lobectomy specimens. Int J Chron Obstruct Pulmon Dis. 2016;11:1521-32. doi: 10.2147/COPD.S107938

76. Ash SY, Harmouche R, Ross JC, et al. Interstitial Features at Chest CT Enhance the Deleterious Effects of Emphysema in the COPDGene Cohort. Radiology. Aug 2018;28 8(2):600-609. doi:10.1148/radiol.2018172688

77. Menon AA, Putman RK, Sanders JL, et al. Interstitial Lung Abnormalities, Emphysema, and Spirometry in Smokers. Chest. Apr 2022;1 61(4):999-1010. doi:10.1016/j.chest.2021.10.034

78. 7 How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General. (CDC (US)) (2010).

79. Huie TJ, Solomon JJ. Emphysema and pulmonary fibrosis: coincidence or conspiracy? Respirology. Nov 2013;18(8):116 3-4. doi:10.1111/resp.12187

80. Selman M, Martinez FJ, Pardo A. Why Does an Aging Smoker's Lung Develop Idiopathic Pulmonary Fibrosis and Not Chronic Obstructive Pulmonary Disease? Am J Respir Crit Care Med. Feb 1 2019;199(3):279 -285. doi:10.1164/rccm.201806-1166PP

81. Cottin V, Nunes H, Brillet PY, et al. Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity. Eur Respir J. Oct 2005;26(4):586-93. doi:10.1183/09031936.05.00021005

82. Antoniou KM, Walsh SL, Hansell DM, et al. Smoking-related emphysema is associated with idiopathic pulmonary fibrosis and rheumatoid lung. Respirology. Nov 2013;18(8 ):1191-6. doi:10.1111/resp.12154

83. Auerbach O, Garfinkel L, Hammond EC. Relation of smoking and age to findings in lung parenchyma: a microscopic study. Chest. Jan 1974;65(1):29-35. doi:10.1378/chest.65.1.29

84. Wells AU, King AD, Rubens MB, Cramer D, du Bois RM, Hansell DM. Lone cryptogenic fibrosing alveolitis: a functional-morphologic correlation based on extent of disease on thin-section computed tomography. Am J Respir Crit Care Med. Apr 1997;155(4):1367-75. doi:10.1164/ajrccm.155.4.9105081

85. Cottin V, Selman M, Inoue Y, et al. Syndrome of Combined Pulmonary Fibrosis and Emphysema: An Official ATS/ERS/JRS/AL AT Research Statement. Am J Respir Crit Care Med. Aug 15 2022;206(4):e7-e41. doi:10.116 4/rccm.202206-1041ST

86. The definition of emphysema. Report of a National Heart, Lung, and Blood Institute, Division of Lung Diseases workshop. Am Rev Respir Dis. Jul 1985;132(1):182-5. doi:10.1164 /arrd.1985.132.1.182

87. Cardoso WV, Sekhon HS, Hyde DM, Thurlbeck WM. Collagen and elastin in human pulmonary emphysema. Am Rev Respir Dis. Apr 1993;147(4):975-81. doi:10.1164/ajrccm/ 147.4.975

88. Wright JL, Tazelaar HD, Churg A. Fibrosis with emphysema. Histopathology. Mar 2011; 58(4):517-24. doi:10.1111/j.1365-2559.2010. 03648.x

89. Katzenstein AL, Mukhopadhyay S, Zanardi C, Dexter E. Clinically occult interstitial fibrosis in smokers: classification and significance of a surprisingly common finding in lobectomy specimens. Hum Pathol. Mar 2010;41(3):316-25. doi:10.1016/j.humpat h.2009.09.003

90. Kawabata Y, Hoshi E, Murai K, et al. Smoking-related changes in the background lung of specimens resected for lung cancer: a semiquantitative study with correlation to postoperative course. Histopathology. Dec 2008;53(6):707-14. doi:10.1111/j.1365-2559. 2008.03183.x

91. Yousem SA. Respiratory bronchiolitis-associated interstitial lung disease with fibrosis is a lesion distinct from fibrotic nonspecific interstitial pneumonia: a proposal. Mod Pathol. Nov 2006;19(11):1474-9. doi:10. 1038/modpathol.3800671

92. Kinoshita Y, Watanabe K, Ishii H, Kushima H, Fujita M, Nabeshima K. Distribution of emphysema and fibrosis in idiopathic pulmonary fibrosis with coexisting emphysema. Histopathology. Jun 2019;74(7):1103-1108. doi:10.1111/his.13831

93. Inomata M, Ikushima S, Awano N, et al. An autopsy study of combined pulmonary fibrosis and emphysema: correlations among clinical, radiological, and pathological features. BMC Pulm Med. Jun 28 2014;14:104 . doi:10.1186/1471-2466-14-104

94. Sangani R, Ghio A, Culp S, Patel Z, Sharma S. Combined Pulmonary Fibrosis Emphysema: Role of Cigarette Smoking and Pulmonary Hypertension in a Rural Cohort. Int J Chron Obstruct Pulmon Dis. 2021;16:1873-1885. doi:10.2147/COPD.S307192

95. Papaioannou AI, Kostikas K, Manali ED, et al. Combined pulmonary fibrosis and emphysema: The many aspects of a cohabitation contract. Respir Med. Aug 2016;117:14-26. doi:10.1016/j.rmed.2016.05.005

96. Ryerson CJ, Hartman T, Elicker BM, et al. Clinical features and outcomes in combined pulmonary fibrosis and emphysema in idiopathic pulmonary fibrosis. Chest. Jul 2013;144(1):234-240. doi:10.1378/chest.12-2403

97. Douglas D, Keating L, Strykowski R, et al. Tobacco smoking is associated with combined pulmonary fibrosis and emphysema and worse outcomes in interstitial lung disease. Am J Physiol Lung Cell Mol Physiol. Aug 1 2023;325(2):L233-L243. doi:10.1152/ajplung.00083.2023

98. Koo HJ, Do KH, Lee JB, Alblushi S, Lee SM. Lung Cancer in Combined Pulmonary Fibrosis and Emphysema: A Systematic Review and Meta-Analysis. PLoS One. 2016;1 1(9):e0161437. doi:10.1371/journal.pone.0161437

99. Chen Q, Liu P, Zhou H, Kong H, Xie W. An increased risk of lung cancer in combined pulmonary fibrosis and emphysema patients with usual interstitial pneumonia compared with patients with idiopathic pulmonary fibrosis alone: a systematic review and meta-analysis. Ther Adv Respir Dis. Jan-Dec 2021; 15:17534666211017050. doi:10.1177/17534666211017050

100. Hata A, Sekine Y, Kota O, Koh E, Yoshino I. Impact of combined pulmonary fibrosis and emphysema on surgical complications and long-term survival in patients undergoing surgery for non-small-cell lung cancer. Int J Chron Obstruct Pulmon Dis. 2016;11:1261-8. doi:10.2147/COPD.S94119

101. Takahashi T, Terada Y, Pasque MK, et al. Clinical Features and Outcomes of Combined Pulmonary Fibrosis and Emphysema After Lung Transplantation. Chest. Nov 2021;160(5) :1743-1750. doi:10.1016/j.chest.2021.06.036

102. Gredic M, Blanco I, Kovacs G, et al. Pulmonary hypertension in chronic obstructive pulmonary disease. Br J Pharmacol. Jan 2021;178(1):132-151. doi:10.1 111/bph.14979

103. Ni H, Wei Y, Yang L, Wang Q. An increased risk of pulmonary hypertension in patients with combined pulmonary fibrosis and emphysema: a meta-analysis. BMC Pulm Med. Jun 21 2023;23(1):221. doi:10.1186/s12 890-023-02425-4

104. Ghio AJ, Hilborn ED, Stonehuerner JG, et al. Particulate matter in cigarette smoke alters iron homeostasis to produce a biological effect. Am J Respir Crit Care Med. Dec 1 2008;178(11):1130-8. doi:10.1164/rccm.200802-334OC

105. Mitchell RS, Vincent TN, Filley GF. Cigarette Smoking, Chronic Bronchitis, and Emphysema. JAMA. Apr 6 1964;188:12-6. doi:10.1001/jama.1964.03060270018004

106. You R, Lu W, Shan M, et al. Nanoparticulate carbon black in cigarette smoke induces DNA cleavage and Th17-mediated emphysema. Elife. Oct 5 2015;4:e0 9623. doi:10.7554/eLife.09623

107. Pratt PC, Jutabha P, Klugh GA. The relationship between pigment deposits and lesions in normal and centrilobular emphysematous lungs. Am Rev Respir Dis. Feb 1963;87:245-56. doi:10.1164/arrd.1963. 87.2.245

108. Lippmann M, Yeates DB, Albert RE. Deposition, retention, and clearance of inhaled particles. Br J Ind Med. Nov 1980;37(4 ):337-62. doi:10.1136/oem.37.4.337

109. Margaritopoulos GA, Vasarmidi E, Jacob J, Wells AU, Antoniou KM. Smoking and interstitial lung diseases. Eur Respir Rev. Sep 2015;24(137):428-35. doi:10.1183/16000617.0050-2015

110. Rao RN, Goodman LR, Tomashefski JF, Jr. Smoking-related interstitial lung disease. Ann Diagn Pathol. Dec 2008;12(6):445-57. doi:10.1016/j.anndiagpath.2008.10.001

111. Churg A, Muller NL, Wright JL. Respiratory bronchiolitis/interstitial lung disease: fibrosis, pulmonary function, and evolving concepts. Arch Pathol Lab Med. Jan 2010;134(1):27-32. doi:10.5858/134.1.27

112. Sieminska A, Kuziemski K. Respiratory bronchiolitis-interstitial lung disease. Orphanet J Rare Dis. Jul 11 2014;9:106. doi:10.1186/s13023-014-0106-8

113. Godbert B, Wissler MP, Vignaud JM. Desquamative interstitial pneumonia: an analytic review with an emphasis on aetiology. Eur Respir Rev. Jun 1 2013;22(128):117-23. doi:10.1183/09059180.00005812

114. Yousem SA, Colby TV, Gaensler EA. Respiratory bronchiolitis-associated interstitial lung disease and its relationship to desquamative interstitial pneumonia. Mayo Clin Proc. Nov 1989;64(11):1373-80. doi:10.1 016/s0025-6196(12)65379-8

115. Desai SR, Ryan SM, Colby TV. Smoking-related interstitial lung diseases: histopathological and imaging perspectives. Clin Radiol. Apr 2003;58(4):259-68. doi:10.10 16/s0009-9260(02)00525-1

116. Diken OE, Sengul A, Beyan AC, Ayten O, Mutlu LC, Okutan O. Desquamative interstitial pneumonia: Risk factors, laboratory and bronchoalveolar lavage findings, radiological and histopathological examination, clinical features, treatment and prognosis. Exp Ther Med. Jan 2019;17(1):587-595. doi:10.3892/et m.2018.7030

117. Sangani RG, Deepak V, Ghio AJ, Patel Z, Alshaikhnassir E, Vos J. Peribronchiolar Metaplasia: A Marker of Cigarette Smoke-Induced Small Airway Injury in a Rural Cohort. Clin Pathol. Jan-Dec 2023;16:2632010X2312 09878. doi:10.1177/2632010X231209878

118. Brown KP. Histopathology of diffuse lung parenchyma epithelial metaplasia in COPD. University of Leicester; 2010. Accessed January 31, 2024. https://hdl.handle.net/2381/9199

119. Higham A, Quinn AM, Cancado JED, Singh D. The pathology of small airways disease in COPD: historical aspects and future directions. Respir Res. Mar 4 2019;20(1):49. doi:10.1186/s12931-019-1017-y

120. Leiter A, Veluswamy RR, Wisnivesky JP. The global burden of lung cancer: current status and future trends. Nat Rev Clin Oncol. Sep 2023;20(9):624-639. doi:10.1038/s41571 -023-00798-3

121. Hohberger LA, Schroeder DR, Bartholmai BJ, et al. Correlation of regional emphysema and lung cancer: a lung tissue research consortium-based study. J Thorac Oncol. May 2014;9(5):639-45. doi:10.1097/JTO.0000000000000144

122. Yang X, Wisselink HJ, Vliegenthart R, et al. Association between Chest CT-defined Emphysema and Lung Cancer: A Systematic Review and Meta-Analysis. Radiology. Aug 2022;304(2):322-330. doi:10.1148/radiol.212904

123. Yong PC, Sigel K, de-Torres JP, et al. The effect of radiographic emphysema in assessing lung cancer risk. Thorax. Sep 2019;74(9):858-864. doi:10.1136/thoraxjnl-20 18-212457

124. Zhang X, Jiang N, Wang L, Liu H, He R. Chronic obstructive pulmonary disease and risk of lung cancer: a meta-analysis of prospective cohort studies. Oncotarget. Sep 29 2017;8(44):78044-78056. doi:10.18632/on cotarget.20351

125. Sun Z, Yang P. Role of imbalance between neutrophil elastase and alpha 1-antitrypsin in cancer development and progression. Lancet Oncol. Mar 2004;5(3):182 -90. doi:10.1016/S1470-2045(04)01414-7

126. Oelsner EC, Carr JJ, Enright PL, et al. Per cent emphysema is associated with respiratory and lung cancer mortality in the general population: a cohort study. Thorax. Jul 2016;71(7):624-32. doi:10.1136/thoraxjnl-2015-207822

127. Sato S, Nakamura M, Shimizu Y, et al. The impact of emphysema on surgical outcomes of early-stage lung cancer: a retrospective study. BMC Pulm Med. Apr 4 2019;19(1):73. doi:10.1186/s12890-019-0839-1

128. Shin S, Park HY, Kim H, et al. Joint effect of airflow limitation and emphysema on postoperative outcomes in early-stage nonsmall cell lung cancer. Eur Respir J. Dec 2016;48(6):1743-1750. doi:10.1183/13993003.01148-2016

129. Goldkorn T, Filosto S. Lung injury and cancer: Mechanistic insights into ceramide and EGFR signaling under cigarette smoke. Am J Respir Cell Mol Biol. Sep 2010;43(3):259 -68. doi:10.1165/rcmb.2010-0220RT

130. Mittal V, El Rayes T, Narula N, McGraw TE, Altorki NK, Barcellos-Hoff MH. The Microenvironment of Lung Cancer and Therapeutic Implications. Adv Exp Med Biol. 2016;890:75-110. doi:10.1007/978-3-319-24932-2_5

131. Murakami J, Ueda K, Sano F, Hayashi M, Nishimoto A, Hamano K. Pulmonary emphysema and tumor microenvironment in primary lung cancer. J Surg Res. Feb 2016;200 (2):690-7. doi:10.1016/j.jss.2015.09.004

132. Saito A, Horie M, Nagase T. TGF-beta Signaling in Lung Health and Disease. Int J Mol Sci. Aug 20 2018;19(8)doi:10.3390/ijms1 9082460

133. Agusti A, Calverley PM, Celli B, et al. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res. Sep 10 2010;11(1):122. doi:10.1186/1465-9921-11-122

134. Dhariwal J, Tennant RC, Hansell DM, et al. Smoking cessation in COPD causes a transient improvement in spirometry and decreases micronodules on high-resolution CT imaging. Chest. May 2014;145(5):1006-1015. doi:10.1378/chest.13-2220

135. Johannessen A, Skorge TD, Bottai M, et al. Mortality by level of emphysema and airway wall thickness. Am J Respir Crit Care Med. Mar 15 2013;187(6):602-8. doi:10.1164/ rccm.201209-1722OC

136. Qaseem A, Wilt TJ, Weinberger SE, et al. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med. Aug 2 2011;155(3):179-91. doi:10.7326/ 0003-4819-155-3-201108020-00008

137. Tylen U, Boijsen M, Ekberg-Jansson A, Bake B, Lofdahl CG. Emphysematous lesions and lung function in healthy smokers 60 years of age. Respir Med. Jan 2000;94(1):38-43. doi:10.1053/rmed.1999.0690

138. Regan EA, Lynch DA, Curran-Everett D, et al. Clinical and Radiologic Disease in Smokers With Normal Spirometry. JAMA Intern Med. Sep 2015;175(9):1539-49. doi:10. 1001/jamainternmed.2015.2735

139. Yasunaga K, Cherot-Kornobis N, Edme JL, et al. Emphysema in asymptomatic smokers: quantitative CT evaluation in correlation with pulmonary function tests. Diagn Interv Imaging. Jun 2013;94(6):609-17. doi:10.1016/j.diii.2013.02.013

140. Kitaguchi Y, Fujimoto K, Kubo K, Honda T. Characteristics of COPD phenotypes classified according to the findings of HRCT. Respir Med. Oct 2006;100(10):1742-52. doi: 10.1016/j.rmed.2006.02.003

141. Robbesom AA, Versteeg EM, Veerkamp JH, et al. Morphological quantification of emphysema in small human lung specimens: comparison of methods and relation with clinical data. Mod Pathol. Jan 2003;16(1):1-7. doi:10.1097/01.MP.0000043519.29370.C2

142. Smoking Cessation: A Report of the Surgeon General ( Department of Health and Human Services, Centers for Disease Control and Prevention) (2020).

143. Willemse BW, Postma DS, Timens W, ten Hacken NH. The impact of smoking cessation on respiratory symptoms, lung function, airway hyperresponsiveness and inflammation. Eur Respir J. Mar 2004;23(3):46 4-76. doi:10.1183/09031936.04.00012704

144. Wright JL, Hobson JE, Wiggs B, Pare PD, Hogg JC. Airway inflammation and peribronchiolar attachments in the lungs of nonsmokers, current and ex-smokers. Lung. 1988;166(5):277-86. doi:10.1007/BF02714058

145. Miller M, Cho JY, Pham A, Friedman PJ, Ramsdell J, Broide DH. Persistent airway inflammation and emphysema progression on CT scan in ex-smokers observed for 4 years. Chest. Jun 2011;139(6):1380-1387. doi:10.13 78/chest.10-0705

146. Pompe E, Strand M, van Rikxoort EM, et al. Five-year Progression of Emphysema and Air Trapping at CT in Smokers with and Those without Chronic Obstructive Pulmonary Disease: Results from the COPDGene Study. Radiology. Apr 2020;295(1):218-226. doi:10. 1148/radiol.2020191429

147. Mohamed Hoesein FA, Zanen P, de Jong PA, et al. Rate of progression of CT-quantified emphysema in male current and ex-smokers: a follow-up study. Respir Res. May 20 2013;14(1):55. doi:10.1186/1465-9921-14-55

148. Ashraf H, Lo P, Shaker SB, et al. Short-term effect of changes in smoking behaviour on emphysema quantification by CT. Thorax. Jan 2011;66(1):55-60. doi:10.1136/thx.2009.132688

149. Scanlon PD, Connett JE, Waller LA, et al. Smoking cessation and lung function in mild-to-moderate chronic obstructive pulmonary disease. The Lung Health Study. Am J Respir Crit Care Med. Feb 2000;161(2 Pt 1):381-90. doi:10.1164/ajrccm.161.2.9901044

150. Mohamed Hoesein FA, Zanen P, van Ginneken B, van Klaveren RJ, Lammers JW. Association of the transfer coefficient of the lung for carbon monoxide with emphysema progression in male smokers. Eur Respir J. Nov 2011;38(5):1012-8. doi:10.1183/0903193 6.00050711

151. Roos-Engstrand E, Ekstrand-Hammarstrom B, Pourazar J, Behndig AF, Bucht A, Blomberg A. Influence of smoking cessation on airway T lymphocyte subsets in COPD. COPD. Apr 2009;6(2):112-20. doi:10.1080/15412550902755358

152. Wan ES, Qiu W, Baccarelli A, et al. Cigarette smoking behaviors and time since quitting are associated with differential DNA methylation across the human genome. Hum Mol Genet. Jul 1 2012;21(13):3073-82. doi:10.1093/hmg/dds135

153. Wan ES, Qiu W, Carey VJ, et al. Smoking-Associated Site-Specific Differential Methylation in Buccal Mucosa in the COPDGene Study. Am J Respir Cell Mol Biol. Aug 2015;53(2):246-54. doi:10.1165/rcmb.20 14-0103OC