CHEST Pulmonary Capillary Hemangiomatosis The Puzzle Takes Shape the late Dr Judah Folkman proposed the Interm1987,“angiogenic diseases” for a group of disorders
that seemed nonneoplastic but which involved persistent angiogenesis.1 This concept followed a rapid expansion in the identification and understanding of endothelial growth factors, vascular cell biology, and the essential role of the microvasculature in health and disease. It was recognized that the microvasculature seemed designed to remain mainly quiescent for many decades, with tight controls limiting capillary growth but with the ability to switch to rapid capillary proliferation in response to hormonal factors, inflammation and injury, or stimuli from tumors.1 Shortly after Dr Folkman’s publication, the first case of familial pulmonary capillary hemangiomatosis (PCH) was described, and another family was described in 2011.2,3 PCH is a rare disorder that was first reported in 1978, with only seven nonrelated cases having been reported by 1998 and a little more than 100 by 2011.2,4,5 The diagnostic histologic feature is the proliferation of capillaries in the pulmonary interstitium.5 However, another essential feature is evidence of invasion by the capillaries into one or more of the pulmonary veins and arteries, alveolar walls and alveolar space, intralobular fibrous septa, and bronchi. Affected areas tend to have a patchy distribution within the lung, and reticulonodular infiltrates may be seen on radiography. Less frequently, the capillaries invade pericardium, pleura, and mediastinal lymph nodes. The first case report described endothelial nuclear pleomorphism and hyperchromasia and suggested that PCH was a form of endothelial neoplasia.4 The clinical picture varies depending on the affected lung structures; therefore, PCH may mimic idiopathic pulmonary arterial hypertension, pulmonary veno-occlusive disease, or atypical interstitial lung disease and may result in a misdiagnosis as airways disease. Once symptoms appear, the course usually is fulminant and fatal. Ultimately, the diagnosis is made by lung biopsy or at lung transplantation or autopsy. Case reports appeared journal.publications.chestnet.org
Editorials CHEST | Volume 145 | Number 2 | February 2014
suggesting therapeutic success with interferon-a and doxycycline, but consistently effective therapy remained elusive.6,7 It is interesting to note that both reported therapies affect angiogenesis. However, the cause of PCH remained a mystery. Twenty-five years after the description of the first family, the mystery is well on its way to being solved. In a landmark study, initially published online in CHEST on October 17, 2013, and now in the current print issue of CHEST (see page 231), Best and colleagues8 describe mutations in the gene for eukaryotic translation initiation factor 2 a kinase 4 (EIF2AK4) (formerly known as GCN2) in a family with PCH and in two other patients with sporadic PCH. EIF2KA4 expression, or lack thereof, contributes to the regulation of angiogenesis, affecting endothelial proliferation and apoptosis resistance. Thus, as was proposed many years ago, PCH may truly be an endothelial neoplasia of the lung.4 The family with the EIF2AK4 mutations transmitted them in an autosomal recessive pattern, as was seen in the original family.2 The authors also studied another patient with familial PCH that had been transmitted in an autosomal dominant pattern and eight other patients with sporadic PCH, but none of them had mutations in EIF2AK4. This does not diminish the significance of the findings; rather, it should spur deeper analysis of EIF2AK4 and its signaling pathways as well as the search for other genes. Indeed, it is now understood that heritable pulmonary arterial hypertension can result from mutations in five different genes, with likely more awaiting discovery.9 Thus, EIF2AK4 mutations should not be expected to account for all cases of PCH. However, just as the recognition of the gene mutations in heritable pulmonary arterial hypertension provided insight into its development, understanding the role of EIF2AK4 will help explain the pathogenesis of PCH. The frequency of PCH in the general population is unknown. In an autopsy series, nearly 6% of subjects had histologic lesions consistent with PCH.10 Presumably, overt disease never develops in most individuals. However, de novo PCH was detected in the lungs from a previously healthy lung donor 3 months after the lungs were used for transplantation.11 The leading current hypothesis for the development of pulmonary arterial hypertension is that the pulmonary microvascular endothelium is injured, or factors CHEST / 145 / 2 / FEBRUARY 2014
197
necessary for its viability and health are altered, followed by emergence of apoptosis-resistant endothelial populations that are dysfunctional and proliferative and that gradually choke off the microcirculation. Plexiform lesions are seen. This process may be considered neoplastic.12 In the current classification of pulmonary hypertension, PCH (group 19) is linked to but not part of pulmonary arterial hypertension (group 1).13 Given the presence of abnormal endothelial proliferation in both, that linkage seems appropriate. Given that PCH involves capillary proliferation, whereas pulmonary arterial hypertension affects mainly the small arteries, and the two disorders have different histologic abnormalities, the separation within the classification is also appropriate. In a remarkable confluence of events, another major piece has just been fitted into the puzzle. Pulmonary veno-occlusive disease (PVOD), also a rare disorder, causes intimal cellular proliferation and fibrosis of pulmonary venules.14,15 PVOD may be familial,16 and other suspected triggers include infections, autoimmune disorders, and drugs and toxins. The nature of the cellular proliferation has not yet been characterized to the same degree as for pulmonary arterial hypertension and PCH, and it is not known if the involved cells are mainly endothelial. Nevertheless, the intimal thickening in the veins has many parallels to that seen in arterioles in PAH. For these reasons, PVOD was also classified in group 19, with PCH. Eyries and colleagues17 have just described 13 families with PVOD and found that all had EIF2AK4 mutations. Moreover, five of 20 seemingly sporadic PVOD cases had the same mutation. Thus, EIF2AK4 represents a clear link between PCH and PVOD. Indeed, histologic overlap of features has previously been described and was again seen in the recent report,17,18 although PCH must not be confused with congested capillaries, as might be seen with downstream venous obstruction. The question is whether PCH and PVOD are distinct disorders or simply different or overlapping manifestations of the same disorder. The reports by Best and colleagues8 and Eyries and colleagues17 would suggest that they are a single disease with a spectrum of pathologies, at least for the autosomal recessive cases. Fitting these pieces of the puzzle marks the beginning of progress toward understanding and being able to attack these devastating illnesses. Finally, a word of appreciation for our geneticist, the late Dr Naomi Fitch. In an era before the tools of modern molecular biology and with only a small family available for analysis, she correctly deduced that the inheritance pattern was autosomal recessive. Our predecessors did so much with so little. David Langleben, MD Montreal, QC, Canada 198
Affiliations: From the Center for Pulmonary Vascular Disease, Division of Cardiology, Jewish General Hospital; and McGill University. Financial/nonfinancial disclosures: The author has reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Correspondence to: David Langleben, MD, Room E-206, Jewish General Hospital, 3755 Cote Ste Catherine, Montreal, QC, H3T 1E2, Canada; e-mail: [email protected] © 2014 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-2513
References 1. Folkman J, Klagsbrun M. Angiogenic factors. Science. 1987; 235(4787):442-447. 2. Langleben D, Heneghan JM, Batten AP, et al. Familial pulmonary capillary hemangiomatosis resulting in primary pulmonary hypertension. Ann Intern Med. 1988;109(2):106-109. 3. Wirbelauer J, Hebestreit H, Marx A, Speer CP. Familial pulmonary capillary hemangiomatosis early in life. Case Rep Pulmonol. 2011;2011:827591. 4. Wagenvoort CA, Beetstra A, Spijker J. Capillary haemangiomatosis of the lungs. Histopathology. 1978;2(6):401-406. 5. Langleben D. Pulmonary capillary hemangiomatosis. In: Peacock AJ, Naeije R, Rubin LJ, eds. Pulmonary Circulation: Diseases and Their Treatment. 3rd ed. London, England: Hodder Arnold; 2011:447-453. 6. White CW, Sondheimer HM, Crouch EC, Wilson H, Fan LL. Treatment of pulmonary hemangiomatosis with recombinant interferon alfa-2a. N Engl J Med. 1989;320(18):1197-1200. 7. Ginns LC, Roberts DH, Mark EJ, Brusch JL, Marler JJ. Pulmonary capillary hemangiomatosis with atypical endotheliomatosis: successful antiangiogenic therapy with doxycycline. Chest. 2003;124(5):2017-2022. 8. Best DH, Sumner KL, Austin ED, et al. EIF2AK4 mutations in pulmonary capillary hemangiomatosis. Chest. 2014;145(2): 231-236. [originally published online October 17, 2013] 9. Ma L, Roman-Campos D, Austin ED, et al. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med. 2013;369(4):351-361. 10. Havlik DM, Massie LW, Williams WL, Crooks LA. Pulmonary capillary hemangiomatosis-like foci. An autopsy study of 8 cases. Am J Clin Pathol. 2000;113(5):655-662. 11. de Perrot M, Waddell TK, Chamberlain D, Hutcheon M, Keshavjee S. De novo pulmonary capillary hemangiomatosis occurring rapidly after bilateral lung transplantation. J Heart Lung Transplant. 2003;22(6):698-700. 12. Rai PR, Cool CD, King JA, et al. The cancer paradigm of severe pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008;178(6):558-564. 13. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(1)(suppl):S43-S54. 14. Cockrill BA, Hales CA. Pulmonary veno-occlusive disease. In: Peacock AJ, Naeije R, Rubin LJ, eds. Pulmonary Circulation. Disease and Their Treatment. London, England: Hodder Arnold, 2011:435-446. 15. Clardy PF, Mandel J. Pulmonary veno-occlusive disease. In: Yuan JX-J, Garcia JGN, Hales CA, Rich S, Archer SL, eds. Textbook of Pulmonary Vascular Disease. New York, NY: Springer, 2011:1169-1181. 16. Davies P, Reid L. Pulmonary veno-occlusive disease in siblings: case report and morphometric study. Hum Pathol. 1982; 13(10):911-915. Editorials
17. Eyries M, Montani D, Girerd B, et al. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension [published online ahead of print December 1, 2013]. Nat Genet. doi:10.1038/ng.2844. 18. Lantuejoul S, Sheppard MN, Corrin B, et al. Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis: a clinicopathologic study of 35 cases. Am J Surg Pathol. 2006;30(7):850-857.
Lung-Gut Cross Talk A Potential Mechanism for Intestinal Dysfunction in Patients With COPD describes a group of conditions that are charCOPD acterized by loss of the functional capacity of the
lungs, which is due to reduced and obstructed airflow.1 This disease exerts a large and increasing health burden worldwide and is often caused by exposure to tobacco smoking. Although primarily considered a respiratory disease, there is growing clinical interest in secondary organ manifestations of COPD, particularly in the GI tract. Indeed, GI disease is more prevalent in patients with COPD than in healthy populations.2 A population-based cohort study performed by Ekbom et al,3 showed a 2.72 times higher risk of Crohn’s disease (an inflammatory bowel disease) in COPD sufferers than that in healthy control subjects, greater than the risk reported for smoking alone. Specific intestinal complications include atrophic gastritis and nutritional absorption deficiency in the small intestine.4,5 Thus, there is a clear link between inflammatory diseases in the respiratory and intestinal systems. However, there have been surprisingly few research studies that have investigated the nature of the cross talk involved, and while several mechanisms have been proposed,6 to date there have been few studies that have aimed to elucidate these connections. The study by Rutten et al7 in this issue (see page 245) provides evidence of intestinal compromise and, importantly, evidence of an associated mechanism for intestinal dysfunction in patients with COPD. They proposed that the increased metabolic demands that are associated with the physical activities of patients with COPD result in a reduction in intestinal perfusion causing ischemia in these tissues. The authors demonstrated increased intestinal permeability in patients with COPD at rest, compared with healthy individuals. However, physical exertion, represented by dayto-day activities, significantly increased the intestinal permeability of the small intestine in patients with COPD, which was assessed by measurement of the excretion of orally ingested sugar probes. This increased permeability was associated with acute enterocyte damage, which occurs rapidly during physical exertion and continues after the completion of activities. Imporjournal.publications.chestnet.org
tantly, there was no evidence of increased enterocyte damage in patients with COPD at rest, suggesting that the physical activity itself precipitates the epithelial damage. Of note, the authors demonstrated that performing the study exercise activities placed a higher metabolic demand on patients with COPD, and that metabolic load, measured as serum lactic acid, correlated with intestinal permeability in these patients. Thus, an intriguing hypothesis presents whereby patients with COPD, unable to cope with the metabolic demand of daily activities, are susceptible to intestinal ischemia and associated enterocyte damage. This is surprising as, although chronic intestinal ischemia promotes intestinal permeability, there is a large body of evidence that suggests that the intestinal mucosa, in particular intestinal epithelial cells, have a number of adaptive pathways to augment acute ischemic damage,8 such as in the study by Rutten et al.7 Indeed, there have been numerous studies that have focused on manipulating these pathways.9 Whether the increased permeability observed overwhelms these protective pathways or whether the pathways are merely dysfunctional has yet to be determined. Of interest in this study was the fact that a minority of the patients with COPD were current smokers. Some important demonstrations of the lung-gut axis have been the observation that active smoking exacerbates Crohn’s disease and that cigarette smoke itself is implicated in GI pathology.10 Cigarette smoke drives bronchitis in patients with COPD as the smoke exposure damages the airway epithelia and epithelial tight junctions,11 and we have hypothesized that this toxic effect may extend systemically to the intestinal epithelium.6 However, it is known that once initiated, the pathogenesis of COPD continues to progress and the patient’s condition continues to deteriorate even upon smoking cessation. Here, Rutten et al7 have demonstrated that epithelial damage may occur in patients with COPD, independently or as a sequelae of cigarette smoking. The suggestion that impaired lung capacity and increased metabolic demand promotes intestinal ischemia offers far-reaching implications across a number of extrapulmonary manifestations of COPD, and future insight may be gained from the investigation of animal models that recapitulate the hallmark features of COPD12 and inflammatory bowel disease.9 In particular, the functional implications of absorptive enterocyte loss in terms of nutrient absorption remain to be determined. Crucially, in the present study, the loss of intestinal integrity in patients with COPD under increased metabolic demand through daily activities may represent an initiating event in the development of GI pathologies that are associated with COPD.7 The mucosal epithelium forms a selective barrier, separating the interstitium and the underlying tissues from the milieu of antigenic material and CHEST / 145 / 2 / FEBRUARY 2014
199
that seemed nonneoplastic but which involved persistent angiogenesis.1 This concept followed a rapid expansion in the identification and understanding of endothelial growth factors, vascular cell biology, and the essential role of the microvasculature in health and disease. It was recognized that the microvasculature seemed designed to remain mainly quiescent for many decades, with tight controls limiting capillary growth but with the ability to switch to rapid capillary proliferation in response to hormonal factors, inflammation and injury, or stimuli from tumors.1 Shortly after Dr Folkman’s publication, the first case of familial pulmonary capillary hemangiomatosis (PCH) was described, and another family was described in 2011.2,3 PCH is a rare disorder that was first reported in 1978, with only seven nonrelated cases having been reported by 1998 and a little more than 100 by 2011.2,4,5 The diagnostic histologic feature is the proliferation of capillaries in the pulmonary interstitium.5 However, another essential feature is evidence of invasion by the capillaries into one or more of the pulmonary veins and arteries, alveolar walls and alveolar space, intralobular fibrous septa, and bronchi. Affected areas tend to have a patchy distribution within the lung, and reticulonodular infiltrates may be seen on radiography. Less frequently, the capillaries invade pericardium, pleura, and mediastinal lymph nodes. The first case report described endothelial nuclear pleomorphism and hyperchromasia and suggested that PCH was a form of endothelial neoplasia.4 The clinical picture varies depending on the affected lung structures; therefore, PCH may mimic idiopathic pulmonary arterial hypertension, pulmonary veno-occlusive disease, or atypical interstitial lung disease and may result in a misdiagnosis as airways disease. Once symptoms appear, the course usually is fulminant and fatal. Ultimately, the diagnosis is made by lung biopsy or at lung transplantation or autopsy. Case reports appeared journal.publications.chestnet.org
Editorials CHEST | Volume 145 | Number 2 | February 2014
suggesting therapeutic success with interferon-a and doxycycline, but consistently effective therapy remained elusive.6,7 It is interesting to note that both reported therapies affect angiogenesis. However, the cause of PCH remained a mystery. Twenty-five years after the description of the first family, the mystery is well on its way to being solved. In a landmark study, initially published online in CHEST on October 17, 2013, and now in the current print issue of CHEST (see page 231), Best and colleagues8 describe mutations in the gene for eukaryotic translation initiation factor 2 a kinase 4 (EIF2AK4) (formerly known as GCN2) in a family with PCH and in two other patients with sporadic PCH. EIF2KA4 expression, or lack thereof, contributes to the regulation of angiogenesis, affecting endothelial proliferation and apoptosis resistance. Thus, as was proposed many years ago, PCH may truly be an endothelial neoplasia of the lung.4 The family with the EIF2AK4 mutations transmitted them in an autosomal recessive pattern, as was seen in the original family.2 The authors also studied another patient with familial PCH that had been transmitted in an autosomal dominant pattern and eight other patients with sporadic PCH, but none of them had mutations in EIF2AK4. This does not diminish the significance of the findings; rather, it should spur deeper analysis of EIF2AK4 and its signaling pathways as well as the search for other genes. Indeed, it is now understood that heritable pulmonary arterial hypertension can result from mutations in five different genes, with likely more awaiting discovery.9 Thus, EIF2AK4 mutations should not be expected to account for all cases of PCH. However, just as the recognition of the gene mutations in heritable pulmonary arterial hypertension provided insight into its development, understanding the role of EIF2AK4 will help explain the pathogenesis of PCH. The frequency of PCH in the general population is unknown. In an autopsy series, nearly 6% of subjects had histologic lesions consistent with PCH.10 Presumably, overt disease never develops in most individuals. However, de novo PCH was detected in the lungs from a previously healthy lung donor 3 months after the lungs were used for transplantation.11 The leading current hypothesis for the development of pulmonary arterial hypertension is that the pulmonary microvascular endothelium is injured, or factors CHEST / 145 / 2 / FEBRUARY 2014
197
necessary for its viability and health are altered, followed by emergence of apoptosis-resistant endothelial populations that are dysfunctional and proliferative and that gradually choke off the microcirculation. Plexiform lesions are seen. This process may be considered neoplastic.12 In the current classification of pulmonary hypertension, PCH (group 19) is linked to but not part of pulmonary arterial hypertension (group 1).13 Given the presence of abnormal endothelial proliferation in both, that linkage seems appropriate. Given that PCH involves capillary proliferation, whereas pulmonary arterial hypertension affects mainly the small arteries, and the two disorders have different histologic abnormalities, the separation within the classification is also appropriate. In a remarkable confluence of events, another major piece has just been fitted into the puzzle. Pulmonary veno-occlusive disease (PVOD), also a rare disorder, causes intimal cellular proliferation and fibrosis of pulmonary venules.14,15 PVOD may be familial,16 and other suspected triggers include infections, autoimmune disorders, and drugs and toxins. The nature of the cellular proliferation has not yet been characterized to the same degree as for pulmonary arterial hypertension and PCH, and it is not known if the involved cells are mainly endothelial. Nevertheless, the intimal thickening in the veins has many parallels to that seen in arterioles in PAH. For these reasons, PVOD was also classified in group 19, with PCH. Eyries and colleagues17 have just described 13 families with PVOD and found that all had EIF2AK4 mutations. Moreover, five of 20 seemingly sporadic PVOD cases had the same mutation. Thus, EIF2AK4 represents a clear link between PCH and PVOD. Indeed, histologic overlap of features has previously been described and was again seen in the recent report,17,18 although PCH must not be confused with congested capillaries, as might be seen with downstream venous obstruction. The question is whether PCH and PVOD are distinct disorders or simply different or overlapping manifestations of the same disorder. The reports by Best and colleagues8 and Eyries and colleagues17 would suggest that they are a single disease with a spectrum of pathologies, at least for the autosomal recessive cases. Fitting these pieces of the puzzle marks the beginning of progress toward understanding and being able to attack these devastating illnesses. Finally, a word of appreciation for our geneticist, the late Dr Naomi Fitch. In an era before the tools of modern molecular biology and with only a small family available for analysis, she correctly deduced that the inheritance pattern was autosomal recessive. Our predecessors did so much with so little. David Langleben, MD Montreal, QC, Canada 198
Affiliations: From the Center for Pulmonary Vascular Disease, Division of Cardiology, Jewish General Hospital; and McGill University. Financial/nonfinancial disclosures: The author has reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Correspondence to: David Langleben, MD, Room E-206, Jewish General Hospital, 3755 Cote Ste Catherine, Montreal, QC, H3T 1E2, Canada; e-mail: [email protected] © 2014 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-2513
References 1. Folkman J, Klagsbrun M. Angiogenic factors. Science. 1987; 235(4787):442-447. 2. Langleben D, Heneghan JM, Batten AP, et al. Familial pulmonary capillary hemangiomatosis resulting in primary pulmonary hypertension. Ann Intern Med. 1988;109(2):106-109. 3. Wirbelauer J, Hebestreit H, Marx A, Speer CP. Familial pulmonary capillary hemangiomatosis early in life. Case Rep Pulmonol. 2011;2011:827591. 4. Wagenvoort CA, Beetstra A, Spijker J. Capillary haemangiomatosis of the lungs. Histopathology. 1978;2(6):401-406. 5. Langleben D. Pulmonary capillary hemangiomatosis. In: Peacock AJ, Naeije R, Rubin LJ, eds. Pulmonary Circulation: Diseases and Their Treatment. 3rd ed. London, England: Hodder Arnold; 2011:447-453. 6. White CW, Sondheimer HM, Crouch EC, Wilson H, Fan LL. Treatment of pulmonary hemangiomatosis with recombinant interferon alfa-2a. N Engl J Med. 1989;320(18):1197-1200. 7. Ginns LC, Roberts DH, Mark EJ, Brusch JL, Marler JJ. Pulmonary capillary hemangiomatosis with atypical endotheliomatosis: successful antiangiogenic therapy with doxycycline. Chest. 2003;124(5):2017-2022. 8. Best DH, Sumner KL, Austin ED, et al. EIF2AK4 mutations in pulmonary capillary hemangiomatosis. Chest. 2014;145(2): 231-236. [originally published online October 17, 2013] 9. Ma L, Roman-Campos D, Austin ED, et al. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med. 2013;369(4):351-361. 10. Havlik DM, Massie LW, Williams WL, Crooks LA. Pulmonary capillary hemangiomatosis-like foci. An autopsy study of 8 cases. Am J Clin Pathol. 2000;113(5):655-662. 11. de Perrot M, Waddell TK, Chamberlain D, Hutcheon M, Keshavjee S. De novo pulmonary capillary hemangiomatosis occurring rapidly after bilateral lung transplantation. J Heart Lung Transplant. 2003;22(6):698-700. 12. Rai PR, Cool CD, King JA, et al. The cancer paradigm of severe pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008;178(6):558-564. 13. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(1)(suppl):S43-S54. 14. Cockrill BA, Hales CA. Pulmonary veno-occlusive disease. In: Peacock AJ, Naeije R, Rubin LJ, eds. Pulmonary Circulation. Disease and Their Treatment. London, England: Hodder Arnold, 2011:435-446. 15. Clardy PF, Mandel J. Pulmonary veno-occlusive disease. In: Yuan JX-J, Garcia JGN, Hales CA, Rich S, Archer SL, eds. Textbook of Pulmonary Vascular Disease. New York, NY: Springer, 2011:1169-1181. 16. Davies P, Reid L. Pulmonary veno-occlusive disease in siblings: case report and morphometric study. Hum Pathol. 1982; 13(10):911-915. Editorials
17. Eyries M, Montani D, Girerd B, et al. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension [published online ahead of print December 1, 2013]. Nat Genet. doi:10.1038/ng.2844. 18. Lantuejoul S, Sheppard MN, Corrin B, et al. Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis: a clinicopathologic study of 35 cases. Am J Surg Pathol. 2006;30(7):850-857.
Lung-Gut Cross Talk A Potential Mechanism for Intestinal Dysfunction in Patients With COPD describes a group of conditions that are charCOPD acterized by loss of the functional capacity of the
lungs, which is due to reduced and obstructed airflow.1 This disease exerts a large and increasing health burden worldwide and is often caused by exposure to tobacco smoking. Although primarily considered a respiratory disease, there is growing clinical interest in secondary organ manifestations of COPD, particularly in the GI tract. Indeed, GI disease is more prevalent in patients with COPD than in healthy populations.2 A population-based cohort study performed by Ekbom et al,3 showed a 2.72 times higher risk of Crohn’s disease (an inflammatory bowel disease) in COPD sufferers than that in healthy control subjects, greater than the risk reported for smoking alone. Specific intestinal complications include atrophic gastritis and nutritional absorption deficiency in the small intestine.4,5 Thus, there is a clear link between inflammatory diseases in the respiratory and intestinal systems. However, there have been surprisingly few research studies that have investigated the nature of the cross talk involved, and while several mechanisms have been proposed,6 to date there have been few studies that have aimed to elucidate these connections. The study by Rutten et al7 in this issue (see page 245) provides evidence of intestinal compromise and, importantly, evidence of an associated mechanism for intestinal dysfunction in patients with COPD. They proposed that the increased metabolic demands that are associated with the physical activities of patients with COPD result in a reduction in intestinal perfusion causing ischemia in these tissues. The authors demonstrated increased intestinal permeability in patients with COPD at rest, compared with healthy individuals. However, physical exertion, represented by dayto-day activities, significantly increased the intestinal permeability of the small intestine in patients with COPD, which was assessed by measurement of the excretion of orally ingested sugar probes. This increased permeability was associated with acute enterocyte damage, which occurs rapidly during physical exertion and continues after the completion of activities. Imporjournal.publications.chestnet.org
tantly, there was no evidence of increased enterocyte damage in patients with COPD at rest, suggesting that the physical activity itself precipitates the epithelial damage. Of note, the authors demonstrated that performing the study exercise activities placed a higher metabolic demand on patients with COPD, and that metabolic load, measured as serum lactic acid, correlated with intestinal permeability in these patients. Thus, an intriguing hypothesis presents whereby patients with COPD, unable to cope with the metabolic demand of daily activities, are susceptible to intestinal ischemia and associated enterocyte damage. This is surprising as, although chronic intestinal ischemia promotes intestinal permeability, there is a large body of evidence that suggests that the intestinal mucosa, in particular intestinal epithelial cells, have a number of adaptive pathways to augment acute ischemic damage,8 such as in the study by Rutten et al.7 Indeed, there have been numerous studies that have focused on manipulating these pathways.9 Whether the increased permeability observed overwhelms these protective pathways or whether the pathways are merely dysfunctional has yet to be determined. Of interest in this study was the fact that a minority of the patients with COPD were current smokers. Some important demonstrations of the lung-gut axis have been the observation that active smoking exacerbates Crohn’s disease and that cigarette smoke itself is implicated in GI pathology.10 Cigarette smoke drives bronchitis in patients with COPD as the smoke exposure damages the airway epithelia and epithelial tight junctions,11 and we have hypothesized that this toxic effect may extend systemically to the intestinal epithelium.6 However, it is known that once initiated, the pathogenesis of COPD continues to progress and the patient’s condition continues to deteriorate even upon smoking cessation. Here, Rutten et al7 have demonstrated that epithelial damage may occur in patients with COPD, independently or as a sequelae of cigarette smoking. The suggestion that impaired lung capacity and increased metabolic demand promotes intestinal ischemia offers far-reaching implications across a number of extrapulmonary manifestations of COPD, and future insight may be gained from the investigation of animal models that recapitulate the hallmark features of COPD12 and inflammatory bowel disease.9 In particular, the functional implications of absorptive enterocyte loss in terms of nutrient absorption remain to be determined. Crucially, in the present study, the loss of intestinal integrity in patients with COPD under increased metabolic demand through daily activities may represent an initiating event in the development of GI pathologies that are associated with COPD.7 The mucosal epithelium forms a selective barrier, separating the interstitium and the underlying tissues from the milieu of antigenic material and CHEST / 145 / 2 / FEBRUARY 2014
199
