- Email: [email protected]
Prognostic Value of Fibroblastic Foci in Patients With Usual Interstitial Pneumonia
Figure 1. Pedigree showing link between IPF and AAT.
was employed to detect genotype in the two IPF-affected and the AAT-affected individuals. Control tests were run to confirm that the specific primers were amplifying the targeted alleles. Our preliminary data in this family confirm the Z genotype of the individual with AAT deficiency. The data further suggest that an AAT Z allele is also present in both IPF patients, which further supports a linkage of familial IPF to chromosome 14.
References 1 Geddes DM, Webley M, Brewerton DA, et al. ␣1-antitrypsin phenotypes in fibrosing alveolitis and rheumatoid arthritis. Lancet 1977; 2:1049 –1051 2 Musk AW, Zilko PJ, Manners P, et al. Genetic studies in familial fibrosing alveolitis. Possible linkage with immunoglobulin allotypes (Gm). Chest 1986; 89:206 –210
Prognostic Value of Fibroblastic Foci in Patients With Usual Interstitial Pneumonia* Kevin R. Flaherty, MD; Thomas V. Colby, MD, FCCP; William D. Travis, MD, FCCP; Galen B. Toews, MD, FCCP; Andrew Flint, MD; Robert L. Strawderman III, ScM, ScD; Arvind Jain, MS; Joseph P. Lynch III, MD, FCCP; and Fernando J. Martinez, MD, FCCP Abbreviations: CI ⫽ confidence interval; FF ⫽ fibroblastic foci; RR ⫽ relative risk; UIP ⫽ usual interstitial pneumonia
(CHEST 2001; 120:76S–77S) interstitial pneumonia (UIP) is a progressive U sual disorder characterized by a poor response to conven-
tional immunosuppressive agents and significant mortality. The histologic hallmark of UIP is fibrosis, typically patchy and subpleural and paraseptal in distribution. Fibroblastic
*From the University of Michigan (Drs. Flaherty, Toews, Flint, Strawderman, Lynch, Martinez, and Mr. Jain), Ann Arbor, MI; the Mayo Clinic (Dr. Colby), Scottsdale, AZ; and the Armed Forces Institute of Pathology (Dr. Travis), Washington, DC. Correspondence to: Fernando J. Martinez, MD, FCCP, 1500 E Medical Center Dr, 3916 Taubman Center, Ann Arbor, MI 48109-0360; e-mail: [email protected] 76S
foci (FF) are interposed between areas of dense fibrosis and relatively normal-appearing lung. FF are thought to represent recent sites of injury where active collagen synthesis/fibrosis is occurring.1 We hypothesized that patients with increased FF at the time of open-lung biopsy would have decreased survival. Three experienced pathologists (T.V.C., W.D.T., A.F.) participated in a review of open-lung biopsy specimens from patients enrolled in our specialized center of research study of pulmonary fibrosis. Patients with a consensus diagnosis of UIP (n ⫽ 85), excluding those associated with a collagen vascular illness to ensure a population of idiopathic pulmonary fibrosis, were subsequently examined (T.V.C. and W.D.T.), and each lobe was given a score of 0 to 3 (absent, 0; mild, 1; moderate, 2; marked, 3) for FF. The interobserver agreement for FF was excellent (weighted , 0.74; 95% confidence interval [CI], 0.63 to 0.84). The results of the two observers were then averaged. The mean lobar FF score was 1.78 ⫾ 0.7, and the mean maximum (highest score in a lobe) FF score was 2.11 ⫾ 0.7. Sixty-three patients underwent biopsies of multiple lobes. As expected (and by definition of UIP), all patients had FF identified in at least one lobe, although there was variability in FF scores between lobes; this was not statistically significant (analysis of variance, p ⫽ 0.47). In 19 patients, the FF score was congruent, while in 44 patients, the score was discordant in the lobes undergoing biopsy. A Cox proportional-hazards model was used to assess the effect of FF score (mean of all lobes or maximal lobar score) for each patient on survival. An increased score for maximal FF was not associated with a worse prognosis, with a relative risk (RR) of 1.04 (p ⫽ 0.86; 95% CI, 0.68 to 1.58). A similar result was noted when the mean of lobar FF scores was examined (RR, 1.06; p ⫽ 0.79; 95% CI, 0.70 to 1.59). This analysis persisted when adjusting for patient age, gender, and smoking history. Interestingly, female sex (RR, 0.42; 95% CI, 0.18 to 0.98) and smoking history (RR, 0.43; 95% CI, 0.20 to 0.93) were associated with improved survival. We conclude that quantification of FF in a wellcharacterized cohort of patients with UIP/idiopathic pulmonary fibrosis does not aid in predicting survival. It is possible, however, that FF may provide prognostic information when patients with varying types of pulmonary fibrosis (UIP and nonspecific interstitial pneumonia) are evaluated together, as recently demonstrated by
Travis et al.2 In addition, multiple biopsy specimens should be obtained due to the heterogeneous distribution of FF.
References 1 Katzenstein ALA, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med 1998; 157:1301–1315 2 Travis WD, Matsui K, Moss J, et al. Idiopathic nonspecific interstitial pneumonia: prognostic significance of cellular and fibrosing patterns. Am J Surg Pathol 2000; 24:19 –33
Extracellular Matrix Remodeling in Idiopathic Pulmonary Fibrosis* Annie Pardo, PhD; and Moise´s Selman, MD, FCCP Abbreviations: IPF ⫽ idiopathic pulmonary fibrosis; MMP ⫽ matrix metalloproteinase; MT ⫽ membrane type; TIMP ⫽ tissue inhibitor of metalloproteinase
(CHEST 2001; 120:77S) pulmonary fibrosis (IPF) is a progressive and I diopathic lethal lung disorder characterized by fibroblast prolif-
eration and extracellular matrix accumulation. The molecular mechanisms behind the aberrant tissue remodeling should involve the families of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs), main mediators of extracellular matrix turnover. We evaluated by immunohistochemistry and in situ hybridization, the presence of collagenases 1, 2, and 3, gelatinases A and B, membrane type (MT)1-MMP, and TIMPs 1, 2, 3, and 4, in 12 IPF lungs and 6 control lungs. Collagenase-1 was localized in alveolar macrophages and type 2 pneumocytes, mainly those lining honeycomb cysts. Collagenase-2 was observed in neutrophils, and collagenase-3 was not detected, even when assayed by reverse transcriptase-polymerase chain reaction. Gelatinase A was noticed in myofibroblasts close to areas of basement membrane disruption. MT1-MMP was observed in widely spaced interstitial cells and in alveolar epithelial cells. Gelatinase B was found in neutrophils and alveolar epithelial cells and, interestingly, in myofibroblasts foci, a finding corroborated in vitro by reverse transcriptasepolymerase chain reaction. TIMP-1 was present in interstitial macrophages and fibroblasts in areas of dense scar tissue, while TIMP-2 was found in myofibroblast. TIMP-3 was localized mainly coupled to the elastic lamina of vessels, revealing the characteristic duplication of this
*From the Facultad de Ciencias, Universidad Nacional Autonoma de Mexico, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico. Correspondence to: Annie Pardo, PhD, Faculty of Sciences, Universidad Nacional Autonoma de Mexico, Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502, CP 14080, Me´xico DF, Me´xico.
structure in pulmonary fibrosis. TIMP-4 was expressed by alveolar epithelial and plasma cells. These findings suggest that in IPF (1) there is a higher expression of TIMPs compared with collagenases in the lung parenchyma, suggesting that a nondegrading fibrillar collagen microenvironment is prevailing; and (2) excessive gelatinases production might play a role in basement membrane disruption, enhancing fibroblast invasion to the alveolar spaces.
Mechanisms of Pulmonary Fibrosis* Conference Summary Robert M. Strieter, MD, FCCP Abbreviations: BALF ⫽ BAL fluid; BOS ⫽ bronchiolitis obliterans syndrome; ECM ⫽ extracellular matrix; IFN ⫽ interferon; IL ⫽ interleukin; IL-1ra ⫽ interleukin-1 receptor antagonist; ILD ⫽ interstitial lung disease; IPF ⫽ idiopathic pulmonary fibrosis; MAP ⫽ mitogen-activated protein; MCP ⫽ monocyte chemoattractant protein; MIP ⫽ macrophage inflammatory protein; MMP ⫽ matrix metalloproteinase; NF ⫽ nuclear factor; NSIP ⫽ nonspecific interstitial pneumonia; PDGF ⫽ plateletderived growth factor; PGE2 ⫽ prostaglandin E2; Th ⫽ T-helper; TGF ⫽ transforming growth factor; TIMP ⫽ tissue inhibitor of metalloproteinase; TNF ⫽ tumor necrosis factor; UIP ⫽ usual interstitial pneumonia
(CHEST 2001; 120:77S– 85S) would first like to thank David Riches and Scott I Worthen for organizing an outstanding meeting and for
inviting me as conference summarizer. The presentations and discussions of mechanisms of pulmonary fibrosis at this meeting have reinforced five major issues. First, there have been and presently are outstanding investigations in the field of pulmonary fibrosis as exemplified by this conference. Second, although these studies have made outstanding contributions to further our understanding of the mechanisms related to pulmonary fibrosis, it is clear that we have the need to further our basic and clinical science knowledge of this complex process. Third, the missing link between basic science research and clinical research is that we lack information regarding the natural history of human pulmonary fibrosis, and we are left with only descriptive “snapshots” of the histopathology of human pulmonary fibrosis. This situation directly impacts on our understanding of the actual pathogenesis of these disorders. Fourth, as Dr. King points out, idiopathic pulmonary fibrosis (IPF) is a devastating disease with a 5-year survival of only 30%. This is potentially related to the fact that fibroblastic foci of granulation tissue and its *From the University of California, Los Angeles School of Medicine, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Los Angeles, CA. Correspondence to: Robert M. Strieter, MD, FCCP, Division of Pulmonary and Critical Care Medicine, Department of Medicine, UCLA School of Medicine, 900 Veteran Ave, 14 –154 Warren Hall, Box 711922, Los Angeles, CA 90095-1922; e-mail: [email protected] CHEST / 120 / 1 / JULY, 2001 SUPPLEMENT
77S
was employed to detect genotype in the two IPF-affected and the AAT-affected individuals. Control tests were run to confirm that the specific primers were amplifying the targeted alleles. Our preliminary data in this family confirm the Z genotype of the individual with AAT deficiency. The data further suggest that an AAT Z allele is also present in both IPF patients, which further supports a linkage of familial IPF to chromosome 14.
References 1 Geddes DM, Webley M, Brewerton DA, et al. ␣1-antitrypsin phenotypes in fibrosing alveolitis and rheumatoid arthritis. Lancet 1977; 2:1049 –1051 2 Musk AW, Zilko PJ, Manners P, et al. Genetic studies in familial fibrosing alveolitis. Possible linkage with immunoglobulin allotypes (Gm). Chest 1986; 89:206 –210
Prognostic Value of Fibroblastic Foci in Patients With Usual Interstitial Pneumonia* Kevin R. Flaherty, MD; Thomas V. Colby, MD, FCCP; William D. Travis, MD, FCCP; Galen B. Toews, MD, FCCP; Andrew Flint, MD; Robert L. Strawderman III, ScM, ScD; Arvind Jain, MS; Joseph P. Lynch III, MD, FCCP; and Fernando J. Martinez, MD, FCCP Abbreviations: CI ⫽ confidence interval; FF ⫽ fibroblastic foci; RR ⫽ relative risk; UIP ⫽ usual interstitial pneumonia
(CHEST 2001; 120:76S–77S) interstitial pneumonia (UIP) is a progressive U sual disorder characterized by a poor response to conven-
tional immunosuppressive agents and significant mortality. The histologic hallmark of UIP is fibrosis, typically patchy and subpleural and paraseptal in distribution. Fibroblastic
*From the University of Michigan (Drs. Flaherty, Toews, Flint, Strawderman, Lynch, Martinez, and Mr. Jain), Ann Arbor, MI; the Mayo Clinic (Dr. Colby), Scottsdale, AZ; and the Armed Forces Institute of Pathology (Dr. Travis), Washington, DC. Correspondence to: Fernando J. Martinez, MD, FCCP, 1500 E Medical Center Dr, 3916 Taubman Center, Ann Arbor, MI 48109-0360; e-mail: [email protected] 76S
foci (FF) are interposed between areas of dense fibrosis and relatively normal-appearing lung. FF are thought to represent recent sites of injury where active collagen synthesis/fibrosis is occurring.1 We hypothesized that patients with increased FF at the time of open-lung biopsy would have decreased survival. Three experienced pathologists (T.V.C., W.D.T., A.F.) participated in a review of open-lung biopsy specimens from patients enrolled in our specialized center of research study of pulmonary fibrosis. Patients with a consensus diagnosis of UIP (n ⫽ 85), excluding those associated with a collagen vascular illness to ensure a population of idiopathic pulmonary fibrosis, were subsequently examined (T.V.C. and W.D.T.), and each lobe was given a score of 0 to 3 (absent, 0; mild, 1; moderate, 2; marked, 3) for FF. The interobserver agreement for FF was excellent (weighted , 0.74; 95% confidence interval [CI], 0.63 to 0.84). The results of the two observers were then averaged. The mean lobar FF score was 1.78 ⫾ 0.7, and the mean maximum (highest score in a lobe) FF score was 2.11 ⫾ 0.7. Sixty-three patients underwent biopsies of multiple lobes. As expected (and by definition of UIP), all patients had FF identified in at least one lobe, although there was variability in FF scores between lobes; this was not statistically significant (analysis of variance, p ⫽ 0.47). In 19 patients, the FF score was congruent, while in 44 patients, the score was discordant in the lobes undergoing biopsy. A Cox proportional-hazards model was used to assess the effect of FF score (mean of all lobes or maximal lobar score) for each patient on survival. An increased score for maximal FF was not associated with a worse prognosis, with a relative risk (RR) of 1.04 (p ⫽ 0.86; 95% CI, 0.68 to 1.58). A similar result was noted when the mean of lobar FF scores was examined (RR, 1.06; p ⫽ 0.79; 95% CI, 0.70 to 1.59). This analysis persisted when adjusting for patient age, gender, and smoking history. Interestingly, female sex (RR, 0.42; 95% CI, 0.18 to 0.98) and smoking history (RR, 0.43; 95% CI, 0.20 to 0.93) were associated with improved survival. We conclude that quantification of FF in a wellcharacterized cohort of patients with UIP/idiopathic pulmonary fibrosis does not aid in predicting survival. It is possible, however, that FF may provide prognostic information when patients with varying types of pulmonary fibrosis (UIP and nonspecific interstitial pneumonia) are evaluated together, as recently demonstrated by
Travis et al.2 In addition, multiple biopsy specimens should be obtained due to the heterogeneous distribution of FF.
References 1 Katzenstein ALA, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med 1998; 157:1301–1315 2 Travis WD, Matsui K, Moss J, et al. Idiopathic nonspecific interstitial pneumonia: prognostic significance of cellular and fibrosing patterns. Am J Surg Pathol 2000; 24:19 –33
Extracellular Matrix Remodeling in Idiopathic Pulmonary Fibrosis* Annie Pardo, PhD; and Moise´s Selman, MD, FCCP Abbreviations: IPF ⫽ idiopathic pulmonary fibrosis; MMP ⫽ matrix metalloproteinase; MT ⫽ membrane type; TIMP ⫽ tissue inhibitor of metalloproteinase
(CHEST 2001; 120:77S) pulmonary fibrosis (IPF) is a progressive and I diopathic lethal lung disorder characterized by fibroblast prolif-
eration and extracellular matrix accumulation. The molecular mechanisms behind the aberrant tissue remodeling should involve the families of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs), main mediators of extracellular matrix turnover. We evaluated by immunohistochemistry and in situ hybridization, the presence of collagenases 1, 2, and 3, gelatinases A and B, membrane type (MT)1-MMP, and TIMPs 1, 2, 3, and 4, in 12 IPF lungs and 6 control lungs. Collagenase-1 was localized in alveolar macrophages and type 2 pneumocytes, mainly those lining honeycomb cysts. Collagenase-2 was observed in neutrophils, and collagenase-3 was not detected, even when assayed by reverse transcriptase-polymerase chain reaction. Gelatinase A was noticed in myofibroblasts close to areas of basement membrane disruption. MT1-MMP was observed in widely spaced interstitial cells and in alveolar epithelial cells. Gelatinase B was found in neutrophils and alveolar epithelial cells and, interestingly, in myofibroblasts foci, a finding corroborated in vitro by reverse transcriptasepolymerase chain reaction. TIMP-1 was present in interstitial macrophages and fibroblasts in areas of dense scar tissue, while TIMP-2 was found in myofibroblast. TIMP-3 was localized mainly coupled to the elastic lamina of vessels, revealing the characteristic duplication of this
*From the Facultad de Ciencias, Universidad Nacional Autonoma de Mexico, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico. Correspondence to: Annie Pardo, PhD, Faculty of Sciences, Universidad Nacional Autonoma de Mexico, Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502, CP 14080, Me´xico DF, Me´xico.
structure in pulmonary fibrosis. TIMP-4 was expressed by alveolar epithelial and plasma cells. These findings suggest that in IPF (1) there is a higher expression of TIMPs compared with collagenases in the lung parenchyma, suggesting that a nondegrading fibrillar collagen microenvironment is prevailing; and (2) excessive gelatinases production might play a role in basement membrane disruption, enhancing fibroblast invasion to the alveolar spaces.
Mechanisms of Pulmonary Fibrosis* Conference Summary Robert M. Strieter, MD, FCCP Abbreviations: BALF ⫽ BAL fluid; BOS ⫽ bronchiolitis obliterans syndrome; ECM ⫽ extracellular matrix; IFN ⫽ interferon; IL ⫽ interleukin; IL-1ra ⫽ interleukin-1 receptor antagonist; ILD ⫽ interstitial lung disease; IPF ⫽ idiopathic pulmonary fibrosis; MAP ⫽ mitogen-activated protein; MCP ⫽ monocyte chemoattractant protein; MIP ⫽ macrophage inflammatory protein; MMP ⫽ matrix metalloproteinase; NF ⫽ nuclear factor; NSIP ⫽ nonspecific interstitial pneumonia; PDGF ⫽ plateletderived growth factor; PGE2 ⫽ prostaglandin E2; Th ⫽ T-helper; TGF ⫽ transforming growth factor; TIMP ⫽ tissue inhibitor of metalloproteinase; TNF ⫽ tumor necrosis factor; UIP ⫽ usual interstitial pneumonia
(CHEST 2001; 120:77S– 85S) would first like to thank David Riches and Scott I Worthen for organizing an outstanding meeting and for
inviting me as conference summarizer. The presentations and discussions of mechanisms of pulmonary fibrosis at this meeting have reinforced five major issues. First, there have been and presently are outstanding investigations in the field of pulmonary fibrosis as exemplified by this conference. Second, although these studies have made outstanding contributions to further our understanding of the mechanisms related to pulmonary fibrosis, it is clear that we have the need to further our basic and clinical science knowledge of this complex process. Third, the missing link between basic science research and clinical research is that we lack information regarding the natural history of human pulmonary fibrosis, and we are left with only descriptive “snapshots” of the histopathology of human pulmonary fibrosis. This situation directly impacts on our understanding of the actual pathogenesis of these disorders. Fourth, as Dr. King points out, idiopathic pulmonary fibrosis (IPF) is a devastating disease with a 5-year survival of only 30%. This is potentially related to the fact that fibroblastic foci of granulation tissue and its *From the University of California, Los Angeles School of Medicine, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Los Angeles, CA. Correspondence to: Robert M. Strieter, MD, FCCP, Division of Pulmonary and Critical Care Medicine, Department of Medicine, UCLA School of Medicine, 900 Veteran Ave, 14 –154 Warren Hall, Box 711922, Los Angeles, CA 90095-1922; e-mail: [email protected] CHEST / 120 / 1 / JULY, 2001 SUPPLEMENT
77S