Mapping and Characterization of Alveolar Cells During Smoking and Chronic Obstructive Disease

Study Overview
=================
Brief Summary
-----------------
To evaluate the regenerative capacities of mesenchymal cells composing the microenvironment of alveolar type 2 cells in a population of patients, undergoing thoracic surgery for suspected cancer, who are smokers with and without COPD compared to non-smokers patients

Detailed Description
-----------------
Chronic obstructive pulmonary diseases (COPD) have a major public health impact, as evidenced by the 250 million patients affected by these diseases and the 50% 5-year mortality for severe stages of chronic obstructive pulmonary disease (COPD). One pathophysiological mechanism of COPD and emphysema is a depletion of alveolar progenitor cells inducing a loss of alveolar-reparation capacities after an aggression. The genesis of these alterations and the mechanisms involved remain unknown. Alveolar type 2 cells (AT2) are the alveolar epithelial progenitor cells. AT2 proliferate and differentiate into alveolar type 1 cells (AT1) which form the alveolar-capillary barrier, along with endothelial cells, through which respiratory gas exchanges take place. The proliferation and differentiation of AT2 into AT1 are under the control of mesenchymal cells and endothelial cells located in close proximity. Together these cells form the alveolar stem cell niche. The characteristics and interactions of the different cell populations have been well described during lung growth, in the normal adult lung or during pulmonary fibrosis; however, participants are poorly described during smoking exposure and chronic obstructive diseases.

Official Title
-----------------
Mapping and Characterization of Alveolar Cells During Smoking and Chronic Obstructive Disease

Conditions
-----------------
Chronic Obstructive Lung Disease, Chronic Obstructive Pulmonary Disease

Intervention / Treatment
-----------------
* Other: Thoracic resection surgery


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 Patient undergoing lung resection surgery (lobectomy, pneumonectomy, segmentectomy) for cancer or suspected cancer Acceptance to participate in the protocol Affiliated to a social security plan Exclusion Criteria: Chronic autoimmune disease Patient under guardianship or curators Neo-adjuvant chemotherapy History of thoracic radiotherapy Pregnant woman Minor patient Person not able to consent Person deprived of liberty

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Thoracic resection surgery<br>Smokers (active or ex-smokers) and non-smokers with COPD and without COPD undergoing thoracic resection surgery | Other: Thoracic resection surgery<br>* Patients undergoing thoracic resection surgery (pneumonectomy, lobectomy, segmentectomy) for cancer or suspected cancer, including smokers (active or ex-smokers) and non-smokers, with COPD and without COPD, and non-smoking patients.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of alveolar organoids | Comparison of the number of alveolar organoids formed 21 days after culture of fibroblasts with alveolar type II cells between smokers with and without COPD and non-smoking patients | through study completion, an average of 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fibroblast proliferation capacity | Evaluated by their doubling time, number of cells collected compared to the number of cells seeded | through study completion, an average of 3 years | 
| Differentiation into myofibroblasts | By immunofluorescence marking: number of alpha-smooth muscle actin (alpha-SMA) + cells compared to total cells | through study completion, an average of 3 years | 
| Fibroblast migration capacity | Evaluated in Boyden chamber | through study completion, an average of 3 years | 
| Modulated signaling pathways in isolated fibroblasts between groups | Evaluated by Ribonucleic acid (RNA) sequencing of fibroblasts | through study completion, an average of 3 years | 
| Modulated signaling pathways in endothelial cells between groups | Evaluated byRibonucleic acid (RNA) sequencing of endothelial cells | through study completion, an average of 3 years | 
| Evaluation of cytokines in fibroblasts supernatant | Evaluated by Luminex Assay | through study completion, an average of 3 years | 
| Tumor progression | By studying the migration and invasion of tumor cells | through study completion, an average of 3 years | 
| Identification of different cell types on total lung | Cell types composing the lung stem cell microenvironment measured by single cell analysis | through study completion, an average of 3 years | 
| Severity of pulmonary emphysema, | Change of lung density assessed by computed tomography scan | At inclusion, every year, up to 5 years after surgery | 
| Type of pulmonary emphysema | Assessed by computed tomography scan : [centro-lobular or pan-lobular, para-septal] | At inclusion, every year, up to 5 years after surgery | 
| Research of pulmonary biomarkers | Searched according to the results obtained during cell cultures (immunohistochemistry, immunofluorescence) | through study completion, an average of 3 years | 
| Identification of biomarkers in the pre and postoperative circulating blood | Evaluated in laboratory by metagenomic analysis of 16s Ribonucleic acid (RNA) of bacteria for cluster analysis that correlate with lung injury and could be prognostic markers | through study completion, an average of 3 years | 
| Identification of biomarkers in the intestinal microbiota | Evaluated in laboratory by metagenomic analysis of 16s Ribonucleic acid (RNA) of bacteria for cluster analysis that correlate with lung injury and could be prognostic markers | through study completion, an average of 3 years | 
| Measurement of Forced expiratory volume at one second (FEV1) | Determine the relationship between respiratory disease phenotype and exercise impact by measurement of Forced expiratory volume at one second (FEV1) | through study completion, an average of 3 years | 
| Measurement of Forced Vital Capacity (FVC ) | Determine the relationship between respiratory disease phenotype and exercise impact by measurement of Forced Vital Capacity (FVC ) | through study completion, an average of 3 years | 
| Measurement of pulmonary diffusion capacity of CO (DLCO) | Determine the relationship between respiratory disease phenotype and exercise impact by measurement of pulmonary diffusion capacity of CO (DLCO) | through study completion, an average of 3 years | 
| Measurement of CO transfer coefficient (KCO) | Determine the relationship between respiratory disease phenotype and exercise impact by measurement of CO transfer coefficient (KCO) | through study completion, an average of 3 years |