T Cells Promote Bronchial Epithelial Cell Secretion of Matrix Metalloproteinase-9 via a C-C Chemokine Receptor Type 2 Pathway: Implications for Chronic Lung Allograft Dysfunction.

Chronic lung allograft dysfunction (CLAD) is the major limitation of long-term survival after lung transplantation. CLAD manifests as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). Alloimmune reactions and epithelial-to-mesenchymal transition have been suggested in BOS. However, little is known regarding the role of allogenicity in epithelial cell differentiation. Primary human bronchial epithelial cells (BECs) were treated with activated T cells in the presence or absence of transforming growth factor (TGF)-ß. The expression of epithelial and mesenchymal markers was investigated. The secretion of inflammatory cytokines and matrix metalloproteinase (MMP)-9 was measured in culture supernatants and in plasma from lung transplant recipients (LTRs): 49 stable, 29 with BOS, and 16 with RAS. We demonstrated that C-C motif chemokine 2 secreted by T cells supports TGF-ß-induced MMP-9 production by BECs after binding to C-C chemokine receptor type 2. Longitudinal investigation in LTRs revealed a rise in plasma MMP-9 before CLAD onset. Multivariate analysis showed that plasma MMP-9 was independently associated with BOS (odds ratio [OR] = 6.19, p = 0.002) or RAS (OR = 3.9, p = 0.024) and predicted the occurrence of CLAD 12 months before the functional diagnosis. Thus, immune cells support airway remodeling through the production of MMP-9. Plasma MMP-9 is a potential predictive biomarker of CLAD.

Alpha1-antitrypsin deficiency in Greece: Focus on rare variants.

PURPOSE: A1Antitrypsin deficiency (AATD) pathogenic mutations are expanding beyond the PI*Z and PI*S to a multitude of rare variants. AIM: to investigate genotype and clinical profile of Greeks with AATD. METHODS: Symptomatic adult-patients with early-emphysema defined by fixed airway obstruction and computerized-tomography scan and lower than normal serum AAT levels were enrolled from reference centers all over Greece. Samples were analyzed in the AAT Laboratory, University of Marburg-Germany. RESULTS: Included are 45 adults, 38 homozygous or compound heterozygous for pathogenic variants and 7 heterozygous. Homozygous were 57.9% male, 65.8% ever-smokers, median (IQR) age 49.0(42.5-58.5) years, AAT-levels 0.20(0.08-0.26) g/L, FEV1(%predicted) 41.5(28.8-64.5). PI*Z, PI*Q0, and rare deficient allele's frequency was 51.3%, 32.9%,15.8%, respectively. PI*ZZ genotype was 36.8%, PI*Q0Q0 21.1%, PI*MdeficientMdeficient 7.9%, PI*ZQ0 18.4%, PI*Q0Mdeficient 5.3% and PI*Zrare-deficient 10.5%. Genotyping by Luminex detected: p.(Pro393Leu) associated with MHeerlen (M1Ala/M1Val); p.(Leu65Pro) with MProcida; p.(Lys241Ter) with Q0Bellingham; p.(Leu377Phefs*24) with Q0Mattawa (M1Val) and Q0Ourem (M3); p.(Phe76del) with MMalton (M2), MPalermo (M1Val), MNichinan (V) and Q0LaPalma (S); p.(Asp280Val) with PLowell (M1Val); PDuarte (M4), YBarcelona (p.Pro39His). Gene-sequencing (46.7%) detected Q0GraniteFalls, Q0Saint-Etienne, Q0Amersfoort(M1Ala), MWürzburg, NHartfordcity and one novel-variant (c.1A>G) named Q0Attikon.Heterozygous included PI*MQ0Amersfoort(M1Ala), PI*MMProcida, PI*Mp.(Asp280Val), PI*MOFeyzin. AAT-levels were significantly different between genotypes (p = 0.002). CONCLUSION: Genotyping AATD in Greece, a multiplicity of rare variants and a diversity of rare combinations, including unique ones were observed in two thirds of patients, expanding knowledge regarding European geographical trend in rare variants. Gene sequencing was necessary for genetic diagnosis. In the future the detection of rare genotypes may add to personalize preventive and therapeutic measures.

[Alpha 1-antitrypsin deficiency]. / Le déficit en alpha 1-antitrypsine.

INTRODUCTION: Pulmonary emphysema and liver disease are the clinical expressions of alpha 1-antitrypsin deficiency, an autosomal recessive genetic disease. STATE OF THE ART: Alpha 1-antitrypsin deficiency is usually associated with the homozygous Z variant of the SERPINA1 gene. Its clinical expression always consists in a substantial reduction of alpha 1-antitrypsin serum concentration and its variants are analyzed by isoelectric focalization or molecular techniques. Assessed by CO transfer alteration and CT scan, risk of pulmonary emphysema is increased by tobacco consumption. Assessed by transient elastography and liver ultrasound, risk of liver disease is increased by alcohol consumption or obesity. Treatment of COPD-associated alpha 1-antitrypsin deficiency does not differ from that of other forms of COPD. In patients presenting with severe deficiency, augmentation therapy with plasma-derived alpha 1-antitrypsin reduces the progression of emphysema, as shown in terms of CT-based lung density metrics. Patients with alpha 1-antitrypsin deficiency with a ZZ genotype should refrain from alcohol or tobacco consumption, and watch their weight; so should their close relatives. PERSPECTIVES: Modulation of alpha 1-antitrypsin liver production offers an interesting new therapeutic perspective. CONCLUSION: Homozygous (Z) variants of the SERPINA1 gene confer an increased risk of pulmonary emphysema and liver disease, particularly among smokers, drinkers and obese persons.

[Updated indications and contraindications in 2022 for lung transplantation in France]. / Transplantation pulmonaire en France : actualisation des indications et contre-indications en 2022.

Lung transplantation (LTx) is the last-resort treatment for end-stage respiratory insufficiency, whatever its origin, and represents a steadily expanding field of endeavor. Major developments have been impelled over the years by painstaking efforts at LTx centers to improve donor and recipient selection, and multifaceted attempts have been made to meet the challenges raised by surgical management, perioperative care, and long-term medical complications. The number of procedures has increased, leading to improved post-LTx prognosis. One consequence of these multiple developments has been a pruning away of contraindications over time, which has, in some ways, complicated the patient selection process. With these considerations in mind, the Francophone Pulmonology Society (Société de Pneumology de Langue Française [SPLF]) has set up a task force to produce up-to-date working guidelines designed to assist pulmonologists in managing end-stage respiratory insufficiency, determining which patients may be eligible for LTx, and appropriately timing LTx-center referral. The task force has examined the most recent literature and evaluated the risk factors that continue to limit patient survival after LTx. Ideally, the objectives of LTx are to prolong life while improving quality of life. The guidelines developed by the task force apply to a limited resource and are consistent with the ethical principles described below.

[Screening for alpha1-antitrypsin deficiency using dried blood spot: Assessment of the first 20 months]. / Dépistage du déficit en alpha1-antitrypsine sur sang capillaire recueilli sur papier-filtre : bilan des 20 premiers mois.

INTRODUCTION: Alpha1-antitrypsin deficiency is a predisposing factor for pulmonary disease and under-diagnosis is a significant problem. The results of a targeted screening in patients with respiratory symptoms possibly indicative of severe deficiency are reported here. METHODS: Data were collected from March 2016 to October 2017 on patients who had a capillary blood sample collected during a consultation with a pulmonologist and sent to the laboratory for processing to determine alpha1-antitrypsin concentration, phenotype and possibly genotype. RESULTS: In 20 months, 3728 test kits were requested by 566 pulmonologists and 718 (19 %) specimens sent: among these, 708 were analyzable and 613 were accompanied by clinical information. Of the 708 samples, 70 % had no phenotype associated with quantitative alpha1- antitrypsin deficiency, 7 % had a phenotype associated with a severe deficiency and 23 % had a phenotype associated with an intermediate deficiency. One hundred and eight patients carried at least one PI*Z allele which is considered to be a risk factor for liver disease. CONCLUSIONS: The results of this targeted screening program for alpha1- antitrypsin deficiency using a dried capillary blood sample reflect improvement in early diagnosis of this deficiency in lung disease with good adherence of the pulmonologists to this awareness campaign.

Lung function in Birt-Hogg-Dubé syndrome: a retrospective analysis of 96 patients.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder caused by mutations in the FLCN gene coding for folliculin. Its clinical expression includes cutaneous fibrofolliculomas, renal tumors, multiple pulmonary cysts, and recurrent spontaneous pneumothoraces. Data on lung function in BHD are scarce and it is not known whether lung function declines over time. We retrospectively assessed lung function at baseline and during follow-up in 96 patients with BHD. RESULTS: Ninety-five percent of BHD patients had multiple pulmonary cysts on computed tomography and 59% had experienced at least one pneumothorax. Mean values of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and total lung capacity were normal at baseline. Mean (standard deviation) residual volume (RV) was moderately increased to 116 (36) %pred at baseline, and RV was elevated > 120%pred in 41% of cases. Mean (standard deviation) carbon monoxide transfer factor (DLco) was moderately decreased to 85 (18) %pred at baseline, and DLco was decreased < 80%pred in 33% of cases. When adjusted for age, gender, smoking and history of pleurodesis, lung function parameters did not significantly decline over a follow-up period of 6 years. CONCLUSIONS: Cystic lung disease in BHD does not affect respiratory function at baseline except for slightly increased RV and reduced DLco. No significant deterioration of lung function occurs in BHD over a follow-up period of 6 years.

[When should respiratory physicians consider lung transplantation for their patients? Inscription criteria for the national waiting list]. / Quand le pneumologue doit-il envisager la greffe pulmonaire pour un de ses patients?

INTRODUCTION: Placing a patient on the national lung transplant waiting list remains a difficult matter, and is more a question of timing than selection of the candidate according to disease-specific criteria. BACKGROUND: The listing criteria for cystic fibrosis are FEV1 less than 30% of the predicted value, hypoxaemia with a PaO2 less than 55 mm Hg and hypercapnia with a PaCO2 over 50 mm Hg. The rate of decline of FEV1, increasing antibiotic requirements and life threatening complications can all accelerate the listing procedure. For primary pulmonary hypertension the criteria are persistent dyspnoea, NYHA grade III or IVA, despite epoprostenol treatment and a 6 minute walk test of less than 250 metres. Sarcoidosis, lymphangioleiomyomatosis, histiocytosis X and connective tissue diseases are rare indications for which the listing criteria are similar to those for the more usual respiratory diseases. VIEWPOINTS: Further therapeutic advances, increased numbers of available organs and changes in the allocation rules will necessitate periodical updates of these selection and listing criteria. CONCLUSION: The optimal time for placing lung transplantation patients who have been referred early in the course of their disease on the waiting list will be determined by clinical experience and individual patient follow-up.

[Characteristics of the patients included in the French cohort of patients with emphysema caused by alpha-1 antitrypsin deficiency]. / Caractéristiques des patients inclus dans la cohorte française de patients emphysémateux déficitaires en alpha-1 antitrypsine.

INTRODUCTION: Alpha-1 antitrypsin deficiency is associated with the occurrence of pulmonary emphysema. The aim of this study is to describe the characteristics of patients with alpha-1 antitrypsin deficiency associated pulmonary emphysema. METHODS: We describe a prospective cohort study including adult patients with alpha-1 antitrypsin deficiency associated pulmonary emphysema confirmed by CT scan living in France. Patients' clinical and functional characteristics, quality of life measures and management were recorded every 6 months during a five-year period. RESULTS: 201 patients were included from 56 centres between 2005 and 2008. The characteristics of 110 patients have been analysed. Mean age was 50 years (SD:11.8), 62.7% were males, 90% were tobacco smokers. The main functional results (% predicted) were: FEV1: 42.8 (19.6), CPT: 128.3 (21.7), CRF: 167.0 (46.0), 6 minute walking distance (meters): 413 (130). 51 (46.4%) patients received augmentation therapy. Augmentation therapy was administered weekly (37.5%), twice a month (35.4%) or monthly (25.5%). Study centre was the only factor associated with the likelihood to received augmentation therapy. CONCLUSIONS: The clinical and functional characteristics as well as management of these patients varied markedly. There is a need for a standardization of the management of patients with alpha-1 antitrypsin deficiency associated pulmonary emphysema.

Expression of the alpha-1-antitrypsin gene in mononuclear phagocytes of normal and alpha-1-antitrypsin-deficient individuals.

To evaluate the contribution of mononuclear phagocytes, and particularly alveolar macrophages, to alpha-1-antitrypsin (alpha 1AT) production in normal and alpha 1AT-deficient individuals, Northern analysis with a human alpha 1AT complementary DNA was used to demonstrate that alpha 1AT messenger RNA (mRNA) can be detected in liver, blood monocytes, and alveolar macrophages. Quantification of alpha 1AT mRNA expression demonstrated that: (a) type PiMM monocytes and alveolar macrophages expressed, respectively, 200-fold and 70-fold less alpha 1AT mRNA per cell than the liver; (b) the level of expression of the alpha 1AT gene was increased during the in vitro maturation of blood monocytes; and (c) blood monocyte and alveolar macrophage levels of expression of the alpha 1AT gene were the same in PiMM and PiZZ individuals. However, the amount of newly synthesized alpha 1AT secreted by ZZ alveolar macrophages was 10 times lower than that secreted by MM alveolar macrophages. Thus, mononuclear phagocytes of PiZZ individuals express a secretory defect in alpha 1AT in a fashion similar to hepatocytes. Not only do mononuclear phagocytes provide a readily accessible cell to evaluate the regulation of alpha 1AT gene expression, but these cells may contribute to the levels of alpha 1AT present in the lower respiratory tract in the normal and ZZ states.

Spontaneous expression of the c-sis gene and release of a platelet-derived growth factorlike molecule by human alveolar macrophages.

Alveolar macrophages from normal individuals and patients with interstitial lung diseases spontaneously expressed a 4.2-kilobase mRNA complementary to the c-sis gene, a proto-oncogene coding for one of the chains of platelet-derived growth factor (PDGF). Concomitantly, these cells released a mediator with the properties of PDGF, including: chemotactic factor for smooth muscle cells whose activity was resistant to heat and acid, but sensitive to reduction; mitogenic (competence) activity for fibroblasts; ability to compete with PDGF for its receptor; and precipitated by an anti-PDGF antibody. While blood monocytes did not contain c-sis mRNA transcripts, monocytes matured in vitro expressed c-sis, consistent with the concept that expression of c-sis occurs during the differentiation of monocytes into alveolar macrophages. Together with the known actions of PDGF, these observations suggest that the c-sis proto-oncogene and its PDGF product are part of the armamentarium available to the alveolar macrophages for normal lung defense and participation in lung inflammation.

[JSRV (jaagsiekte sheep retrovirus) and ovine pulmonary carcinoma]. / JSRV (jaagsiekte sheep retrovirus) et cancer du poumon associé chez le mouton.

JSRV (jaagsiekte sheep retrovirus) is a betaretrovirus, infecting small ruminants. This virus is responsible for the development of pulmonary adenocarcinoma, by the transformation of epithelial cells of the bronchioli and alveoli. This animal cancer is related to human bronchioloalveolar cancer (BAC), a specific form of human lung cancer for which a viral etiology has been proposed for several decades. In small ruminants JSRV interacts with the cells through the Hyal2 receptor. JSRV genome is simple and does not contain already known oncogene. It is now well established that the envelope protein is oncogenic by itself, via the cytoplasmic domain of the transmembrane glycoprotein and some domains of the surface glycoprotein. Activation of the PI3K/Akt and MAPK pathways participates to the envelope-induced transformation. The tumour development is associated with telomerase activation.

[Indications of lung transplantation: Patients selection, timing of listing, and choice of procedure]. / Indications de la transplantation pulmonaire : sélection des candidats, critères d'inscription en liste d'attente, choix du type d'intervention.

Lung transplantation (LT) is now considered as an excellent treatment option for selected patients with end-stage pulmonary diseases, such as COPD, cystic fibrosis, idiopathic pulmonary fibrosis, and pulmonary arterial hypertension. The 2 goals of LT are to provide a survival benefit and to improve quality of life. The 3-step decision process leading to LT is discussed in this review. The first step is the selection of candidates, which requires a careful examination in order to check absolute and relative contraindications. The second step is the timing of listing for LT; it requires the knowledge of disease-specific prognostic factors available in international guidelines, and discussed in this paper. The third step is the choice of procedure: indications of heart-lung, single-lung, and bilateral-lung transplantation are described. In conclusion, this document provides guidelines to help pulmonologists in the referral and selection processes of candidates for transplantation in order to optimize the outcome of LT.

[Graft-versus-host disease, a rare complication of lung transplantation]. / La maladie du greffon contre l'hôte, graft-versus-host disease, une complication exceptionnelle de la transplantation pulmonaire.

Graft-versus-host disease (GVHD) is a classic and frequent multisystemic complication of bone marrow allografts. It has also been reported after the transplantation of solid organs such as the liver or gut. Recent cases of GVHD have been reported after lung and heart-lung transplant. Skin, liver, gastrointestinal tract and bone marrow are the organ preferentially affected by GVHD. Corticosteroid is the first line treatment of GVHD. The prognosis reported in solid organ transplants is poor with infectious complications favoured by immunosuppressive therapy. In this article, we report a case of a patient with cystic fibrosis who presented a probable GVHD 18 months after a lung transplant and a literature review of similar cases.

Pathology of human bronchioloalveolar carcinoma and its relationship to the ovine disease.

Lung cancer is a leading cause of cancer with a poor prognosis. Bronchioloalveolar carcinoma (BAC) is a rare tumor that has always intrigued physicians. Since the last World Health Organization classification the pathology has been clarified; BAC per se is an adenocarcinoma with a pure bronchioloalveolar growth pattern and appears as an in situ alveolar adenocarcinoma. More usually BAC is a clinically recognizable entity presenting as multi-focal nodules evolving towards pneumonia associated with pulmonary shunting. Pathology is that of a multifocal mixed adenocarcinoma: bronchioloalveolar and papillar. Whatever the stage, survival is better than in other forms of non-small cell lung cancer (NSCLC). The true frequency of BAC is unknown, although it is a rare form of lung cancer; smoking cannot be excluded as a risk factor. It appears that p53 and ras genes are less often mutated than in other lung adenocarcinomas, suggesting that the cellular mechanisms involved are different. Ovine pulmonary adenocarcinoma (OPA) presents with the same symptoms as BAC in humans and is caused by a betaretrovirus Jaagsiekte sheep retrovirus. Very early on, clinical and histological similarities with human BAC were stressed. A recent series of OPA described, according to the third edition of the WHO classification for human lung cancer, mixed adenocarcinoma, BAC and papillary and/or acinar carcinoma. An immunohistochemical study suggested that some human pulmonary tumors (including BAC) may be associated with a Jaagsiekte sheep retrovirus-related retrovirus,but so far no molecular study has confirmed this observation. Thus, OPA is an exquisite model of carcinogenesis for human lung adenocarcinomas.

Goat endothelial cells may be infected in vitro by transmigration of caprine arthritis-encephalitis virus-infected leucocytes.

The caprine arthritis-encephalitis lentivirus (CAEV) causes a lifelong persistent infection in goats, and induces infiltrations of leucocytes and tissue reorganization in target organs, with a cyclical pattern of viral expression. The mammary gland is an important site of infection, associated with mother-to-kid transmission by infected cells in colostrum and milk. The monocyte/macrophage is the principal target cell, but other cell types, including epithelial and endothelial cells and fibroblasts, are susceptible to in vitro infection with varying levels of viral replication. Such cells, perhaps at specific differentiation states, might play a role in the regulation and transfer of in vivo infection in target organs. In this paper we describe the in vitro infection of endothelial cell monolayers by the transmigration of monocytes carrying the CAEV provirus. The infected endothelial cells progress to expression of the viral p30 capsid antigen, suggesting viral proliferation. Such a process occurring in vivo during angiogenesis and leucocyte homing to the mammary gland in the final third of mammogenesis, might contribute to viral spread in this crucial target organ.