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Pulmonary Alveolar Proteinosis

1998; Elsevier BV; Volume: 113; Issue: 2 Linguagem: Inglês

10.1378/chest.113.2.563-a

1931-3543

Seán Gaine, Aengus O’Marcaigh,

Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis

To the EditorWe read with interest the report by Parker and Novotny (May 1997)1Parker LA Novotny DB Recurrent alveolar proteinosis following double lung transplantation.Chest. 1997; 111: 1457-1458Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar regarding the recurrence of pulmonary alveolar proteinosis (PAP) after double lung transplantation. Although the authors acknowledge that the disorder in this case might result from diminished alveolar macrophage function and hypothesize that this might be caused by a primary defect in circulating monocytes, they state that the fundamental cellular alteration has yet to be determined. The molecular defect in a murine model of PAP has been established. It supports the authors' hypothesis and has a direct bearing on the treatment and outcome of this case.Mice bearing a homozygous targeted disruption of the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene develop PAP at approximately 1 year of age.2Dranoff G Crawford AD Sadelain M et al.Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary homeostasis.Science. 1994; 264: 713-716Crossref PubMed Scopus (748) Google Scholar An identical phenotype has been observed in mice with a targeted disruption of the common beta chain of the GM-CSF receptor (GMR 'c).3Nishinakamura R Nakayama N Hirabayashi Y et al.Mice deficient for the IL-3/GM-CSF/IL-5 beta c receptor exhibit lung pathology and impaired immune response, while beta IL3 receptor-deficient mice are normal.Immunity. 1995; 2: 211-222Abstract Full Text PDF PubMed Scopus (271) Google Scholar More recently, defective expression of the GMR 'c has been shown in several human patients with PAP,4Dirksen U Nishinakamura R Murray R et al.Defective GM-CSF-IL3-IL5 receptor common beta chain expression associated with human pulmonary alveolar proteinosis with or without AML and its correlation by hematopoietic stem cell transplantation.Blood. 1996; 88 (suppl 1): 1-2Google Scholar perhaps as a result of germline mutation of the GMR 'c gene. These data suggest that a subgroup of individuals with idiopathic PAP (perhaps including the patient reported by Parker and Novotny) have a deficiency of GM-CSF or its receptor. Bone marrow transplantation can reverse the lung disease in GMR −/− mice, thus indicating that this form of PAP is clearly a disorder of bone marrow-derived monocytes.5Nishinakamura R Wiler R Dirksen U et al.The pulmonary alveolar proteinosis in granulocyte macrophage colony-stimulating factor/interleukins 3/5 beta c receptor-deficient mice is reversed by bone marrow transplantation.J Exp Med. 1996; 183: 2657-2662Crossref PubMed Scopus (132) Google Scholar Therefore, it is not surprising that PAP might recur after lung transplantation in these cases. This case illustrates the need to consider a congenital defect in GM-CSF signaling as a cause of PAP before lung transplantation, and introduces the possibility of bone marrow transplantation as a potentially curative treatment for early PAP in these patients. To the EditorWe read with interest the report by Parker and Novotny (May 1997)1Parker LA Novotny DB Recurrent alveolar proteinosis following double lung transplantation.Chest. 1997; 111: 1457-1458Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar regarding the recurrence of pulmonary alveolar proteinosis (PAP) after double lung transplantation. Although the authors acknowledge that the disorder in this case might result from diminished alveolar macrophage function and hypothesize that this might be caused by a primary defect in circulating monocytes, they state that the fundamental cellular alteration has yet to be determined. The molecular defect in a murine model of PAP has been established. It supports the authors' hypothesis and has a direct bearing on the treatment and outcome of this case.Mice bearing a homozygous targeted disruption of the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene develop PAP at approximately 1 year of age.2Dranoff G Crawford AD Sadelain M et al.Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary homeostasis.Science. 1994; 264: 713-716Crossref PubMed Scopus (748) Google Scholar An identical phenotype has been observed in mice with a targeted disruption of the common beta chain of the GM-CSF receptor (GMR 'c).3Nishinakamura R Nakayama N Hirabayashi Y et al.Mice deficient for the IL-3/GM-CSF/IL-5 beta c receptor exhibit lung pathology and impaired immune response, while beta IL3 receptor-deficient mice are normal.Immunity. 1995; 2: 211-222Abstract Full Text PDF PubMed Scopus (271) Google Scholar More recently, defective expression of the GMR 'c has been shown in several human patients with PAP,4Dirksen U Nishinakamura R Murray R et al.Defective GM-CSF-IL3-IL5 receptor common beta chain expression associated with human pulmonary alveolar proteinosis with or without AML and its correlation by hematopoietic stem cell transplantation.Blood. 1996; 88 (suppl 1): 1-2Google Scholar perhaps as a result of germline mutation of the GMR 'c gene. These data suggest that a subgroup of individuals with idiopathic PAP (perhaps including the patient reported by Parker and Novotny) have a deficiency of GM-CSF or its receptor. Bone marrow transplantation can reverse the lung disease in GMR −/− mice, thus indicating that this form of PAP is clearly a disorder of bone marrow-derived monocytes.5Nishinakamura R Wiler R Dirksen U et al.The pulmonary alveolar proteinosis in granulocyte macrophage colony-stimulating factor/interleukins 3/5 beta c receptor-deficient mice is reversed by bone marrow transplantation.J Exp Med. 1996; 183: 2657-2662Crossref PubMed Scopus (132) Google Scholar Therefore, it is not surprising that PAP might recur after lung transplantation in these cases. This case illustrates the need to consider a congenital defect in GM-CSF signaling as a cause of PAP before lung transplantation, and introduces the possibility of bone marrow transplantation as a potentially curative treatment for early PAP in these patients. We read with interest the report by Parker and Novotny (May 1997)1Parker LA Novotny DB Recurrent alveolar proteinosis following double lung transplantation.Chest. 1997; 111: 1457-1458Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar regarding the recurrence of pulmonary alveolar proteinosis (PAP) after double lung transplantation. Although the authors acknowledge that the disorder in this case might result from diminished alveolar macrophage function and hypothesize that this might be caused by a primary defect in circulating monocytes, they state that the fundamental cellular alteration has yet to be determined. The molecular defect in a murine model of PAP has been established. It supports the authors' hypothesis and has a direct bearing on the treatment and outcome of this case. Mice bearing a homozygous targeted disruption of the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene develop PAP at approximately 1 year of age.2Dranoff G Crawford AD Sadelain M et al.Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary homeostasis.Science. 1994; 264: 713-716Crossref PubMed Scopus (748) Google Scholar An identical phenotype has been observed in mice with a targeted disruption of the common beta chain of the GM-CSF receptor (GMR 'c).3Nishinakamura R Nakayama N Hirabayashi Y et al.Mice deficient for the IL-3/GM-CSF/IL-5 beta c receptor exhibit lung pathology and impaired immune response, while beta IL3 receptor-deficient mice are normal.Immunity. 1995; 2: 211-222Abstract Full Text PDF PubMed Scopus (271) Google Scholar More recently, defective expression of the GMR 'c has been shown in several human patients with PAP,4Dirksen U Nishinakamura R Murray R et al.Defective GM-CSF-IL3-IL5 receptor common beta chain expression associated with human pulmonary alveolar proteinosis with or without AML and its correlation by hematopoietic stem cell transplantation.Blood. 1996; 88 (suppl 1): 1-2Google Scholar perhaps as a result of germline mutation of the GMR 'c gene. These data suggest that a subgroup of individuals with idiopathic PAP (perhaps including the patient reported by Parker and Novotny) have a deficiency of GM-CSF or its receptor. Bone marrow transplantation can reverse the lung disease in GMR −/− mice, thus indicating that this form of PAP is clearly a disorder of bone marrow-derived monocytes.5Nishinakamura R Wiler R Dirksen U et al.The pulmonary alveolar proteinosis in granulocyte macrophage colony-stimulating factor/interleukins 3/5 beta c receptor-deficient mice is reversed by bone marrow transplantation.J Exp Med. 1996; 183: 2657-2662Crossref PubMed Scopus (132) Google Scholar Therefore, it is not surprising that PAP might recur after lung transplantation in these cases. This case illustrates the need to consider a congenital defect in GM-CSF signaling as a cause of PAP before lung transplantation, and introduces the possibility of bone marrow transplantation as a potentially curative treatment for early PAP in these patients.