Smoking-Related “Interstitial” Lung Disease Open Access

Human lung tissue responds to injury with a combination of destruction, remodeling, and repair that is manifest by airspace enlargement and laying down of collagen and elastin.^1,2  The process of remodeling and repair has been well documented as a response to the inflammation and destruction from cigarette smoke that involves all compartments of the respiratory system from the conducting airways to the alveolar walls.³  The inflammation, destruction, remodeling, and repair from inhaled cigarette smoke are reflected radiologically and histologically as a variety of airway and parenchymal alterations. These alterations have been described over decades as separate diseases, including emphysema,⁴  respiratory bronchiolitis,³  respiratory bronchiolitis–interstitial lung disease,⁵  desquamative interstitial pneumonia,⁶  and pulmonary Langerhans' cell histiocytosis.⁷  Small-airway injury, including submucosal and adventitial fibrosis, remodeling evidenced by distortion, and increased bronchus-associated lymphoid tissue,^8,9  along with thickening of walls of small arteries and arterioles,^9–11  are well-recognized histologic findings in cigarette smokers.

It has only recently been acknowledged that the range of lung injury from cigarette smoke is wider than generally accepted,¹²  in particular, there is increasing recognition that fibrosis of alveolar walls occurs in smokers. As a result, lesions called combined pulmonary fibrosis and emphysema,¹³  respiratory bronchiolitis–interstitial lung disease with fibrosis,¹⁴  airspace enlargement with fibrosis,¹⁵  and clinically occult smoking-related interstitial fibrosis¹⁶  have been added to our lexicon of smoking-related lung injury, again as separate entities. That alveolar wall fibrosis occurs in smokers should not be a surprise. There is long-standing evidence that fibrosis of alveolar walls is related to cigarette smoke exposure. This has been documented in animal^17–20  and human^10,21–24  studies. Collectively, these studies demonstrate not only that cigarette smoke causes alveolar wall fibrosis as evidenced by increased elastic and collagen content, but also that fibrosis increases with time and intensity of exposure. From the study of Auerbach et al¹⁰  in 1963, to the article by Katzenstein et al¹⁶  in 2010, there are at least 5 decades of studies providing evidence that links cigarette smoke exposure to the development of alveolar wall fibrosis.

The clinical significance of fibrosis in dyspneic cigarette smokers is controversial. However, there is consistent evidence that smokers who have emphysema and fibrosis can be extremely dyspneic and may present with normal flow rates on spirometry, normal total lung capacity, and strikingly low diffusion capacity.^25,26  Destruction of lung parenchyma by emphysema reduces elastic recoil of the lung, resulting in reduced flow rates, air trapping, and increased total lung capacity. The opposite occurs with lung fibrosis, which increases elastic recoil of the lung, resulting in increased flow rates and reduced total lung capacity. When emphysema and fibrosis occur together, total lung capacity and flow rates tend to normalize. Both emphysema and fibrosis, however, reduce diffusing capacity, and in combination, the reduction in diffusing capacity is additive. Consequently, patients are dyspneic out of proportion to their spirometric findings. This constellation of dyspnea, normal spirometry findings, and low diffusing capacity often prompts the clinical decision to subject dyspneic smokers to open lung biopsy. The presence of normal spirometry findings in dyspneic cigarette smokers has led to an erroneous assumption that the fibrosis commonly found on biopsy in these patients is clinically insignificant.^14,16,27  In our experience, a substantial percentage of cigarette smokers who undergo open lung biopsy because of dyspnea demonstrate normal flow rates and markedly reduced diffusion capacity. Some meet the criteria for usual interstitial pneumonia both on chest computed tomography (CT) and lung biopsy, a finding also reported by Katzenstein et al,¹⁶  which is not unexpected as smoking is considered to be a risk factor for idiopathic pulmonary fibrosis.^28,29  Many, however, demonstrate a combination of emphysema and fibrosis similar to that described by Yousem¹⁴  and Katzenstein et al.¹⁶  Progression of disease in smokers with this type of fibrosis appears to be slower than in patients with idiopathic pulmonary fibrosis.^14,16  Chest CT often shows evidence of both emphysema and fibrosis even when the spirometry findings are normal (Figure, a and b). However, chest CT, including high-resolution studies, may be insensitive in diffuse fibrosis and the only hint is provided by the presence of emphysematous spaces that are unusually well demarcated because of the surrounding fibrotic lung.

As described and referenced in the preceding paragraphs, the histologic appearance of lung injury secondary to cigarette smoke is a constellation of findings that includes smokers' macrophages within airspaces, which may be airway centered (respiratory bronchiolitis) or diffuse (desquamative interstitial pneumonia) in distribution; emphysema; small-airway injury evidenced by submucosal and adventitial fibrosis, remodeling that results in distortion, and increased bronchus-associated lymphoid tissue; thickening of walls of small arteries and arterioles; stellate cellular and/or fibrotic lesions of pulmonary Langerhans' cell histiocytosis; and alveolar wall fibrosis (Figure, c through g). Currently, we attempt to package this array of findings into separate categories for diagnosis.³⁰  However, Hansell and Nicholson¹²  emphasize the frequent coexistence of smoking-related lung diseases, and in practice, open lung biopsies from smokers more often than not display a combination of histologic findings that cross the boundaries of our established diagnostic categories. The terms smoking-related interstitial lung disease and smoking-related interstitial pneumonia are used in an attempt to bring together coexisting histologic findings into a single diagnosis.³⁰  Although useful as umbrella terms, the terms are incomplete descriptions in that they suggest the injury from smoking is entirely interstitial, and they ignore the importance of smokers' macrophages in the pathogenesis of cigarette smoke–induced lung injury.³¹  The presence of constrictive historical categories has to some degree impeded progress in our understanding of smoking-related lung injury. The recent expansion in descriptive language highlights the need for reassessment of the range of injury related to cigarette smoke that includes all compartments of the respiratory system from the conducting airways to the alveolar walls. Rigorous multidisciplinary investigation^8,26,32  will be required to fully understand the nature and clinical implication of the multiple interrelated components of smoking-related lung injury. In the meantime, smoking-related alveolar wall fibrosis is a well-supported concept and a clinically important form of lung injury.