Lung injury pathways: Adenosine receptor 2B signaling limits development of ischemic bronchiolitis obliterans organizing pneumonia.

Purpose/Aim of the Study: Adenosine signaling was studied in bronchiolitis obliterans organizing pneumonia (BOOP) resulting from unilateral lung ischemia. MATERIALS AND METHODS: Ischemia was achieved by either left main pulmonary artery or complete hilar ligation. Sprague-Dawley (SD) rats, Dahl salt sensitive (SS) rats and SS mutant rat strains containing a mutation in the A2B adenosine receptor gene (Adora2b) were studied. Adenosine concentrations were measured in bronchoalveolar lavage (BAL) by HPLC. A2A (A2AAR) and A2B adenosine receptor (A2BAR) mRNA and protein were quantified. RESULTS: Twenty-four hours after unilateral PA ligation, BAL adenosine concentrations from ischemic lungs were increased relative to contralateral lungs in SD rats. A2BAR mRNA and protein concentrations were increased after PA ligation while miR27a, a negatively regulating microRNA, was decreased in ischemic lungs. A2AAR mRNA and protein concentrations remained unchanged following ischemia. A2BAR protein was increased in PA ligated lungs of SS rats after 7 days, and 4 h after complete hilar ligation in SD rats. SS-Adora2b mutants showed a greater extent of BOOP relative to SS rats, and greater inflammatory changes. CONCLUSION: Increased A2BAR and adenosine following unilateral lung ischemia as well as more BOOP in A2BAR mutant rats implicate a protective role for A2BAR signaling in countering ischemic lung injury.

Lung disease and ulcerative colitis--mesalazine-induced bronchiolitis obliterans with organizing pneumonia or pulmonary manifestation of inflammatory bowel disease?

Ulcerative colitis can be associated with numerous extraintestinal organ manifestations. Pulmonary disease in inflammatory bowel disease (IBD) is supposed to be a rare entity and has to be distinguished from infectious complications and side-effects of medications used in the treatment of IBD. We present the case of a 20-year-old male patient with ulcerative colitis and a 4-week history of respiratory symptoms, malaise, fever and respiratory insufficiency under a medication with mesalazine. Computed tomography showed bilateral subpleural consolidations, bronchoscopy revealed signs of acute bronchitis. The diagnostic work-up ruled out an infectious cause. Under the tentative diagnosis of a mesalazine-induced bronchiolitis obliterans with organizing pneumonia (BOOP) the medication with mesalazine was withdrawn and the patient received a corticosteroid trial. The symptoms quickly improved and prednisone was tapered and stopped after 6 months. Unexpectedly, lung function after complete resolution of respiratory symptoms revealed a residual obstructive ventilatory defect that might be due to an asymptomatic pulmonary manifestation of ulcerative colitis. A review of the literature shows that pulmonary manifestations in IBD as well as pulmonary toxicity of mesalazine might not be as rare as expected and should be included as differential diagnoses in the work-up of respiratory symptoms in patients with IBD. A pragmatic therapeutic approach is reasonable in critically ill patients as it is not always easy to distinguish both entities.

Amiodarone-induced organizing pneumonia mimicking COVID-19: a case report.

BACKGROUND: Differential diagnosis of interstitial lung diseases (ILDs) during the COVID-19 pandemic is difficult, due to similarities in clinical and radiological presentation between COVID-19 and other ILDs on the one hand, and frequent false-negative swab results on the other. We describe a rare form of interstitial and organizing pneumonia resembling COVID-19, emphasizing some key aspects to focus on to get the right diagnosis and treat the patient properly. CASE PRESENTATION: A 76-year-old man presented with short breath and dry cough in the midst of the COVID-19 outbreak. He showed bilateral crackles and interstitial-alveolar opacities on X-ray, corresponding on computed tomography (CT) to extensive consolidations with air bronchograms, surrounded by ground glass opacities (GGO). Although his throat-and-nasopharyngeal swab tested negative, the picture was overall compatible with COVID-19. On the other hand, he showed subacute, rather than hyperacute, clinical onset; few and stable parenchymal consolidations, rather than patchy and rapidly evolving GGO; pleural and pericardial thickening, pleural effusion, and lymph node enlargement, usually absent in COVID-19; and peripheral eosinophilia, rather than lymphopenia, suggestive of hypersensitivity. In the past year, he had been taking amiodarone for a history of ventricular ectopic beats. CT scans, in fact, highlighted hyperattenuation areas suggestive of amiodarone pulmonary accumulation and toxicity. Bronchoalveolar lavage fluid (BALF) investigation confirmed the absence of coronavirus genome in the lower respiratory tract; conversely, high numbers of foamy macrophages, eosinophils, and cytotoxic T lymphocytes with low CD4/CD8 T-cell ratio were detected, confirming the hypothesis of amiodarone-induced cryptogenic organizing pneumonia. Timely discontinuation of amiodarone and initiation of steroid therapy led to resolution of respiratory symptoms, systemic inflammation, and radiographic opacities. CONCLUSIONS: A comprehensive analysis of medical and pharmacological history, clinical onset, radiologic details, and peripheral and BALF cellularity, is required for a correct differential diagnosis and management of ILDs in the COVID-19 era.

T-cell depletion prevents from bronchiolitis obliterans and bronchiolitis obliterans with organizing pneumonia after allogeneic hematopoietic stem cell transplantation with related donors.

Bronchiolitis obliterans (BO) and bronchiolitis obliterans organizing pneumonia (BOOP) are late-onset non-infectious pulmonary complications (LONIPCs) following allogeneic hematopoietic stem cell transplantation (HSCT). In the present study 10 of 197 conventionally prepared stem cell recipients developed BOOP after 365 days and 6 patients developed BO 333 days post-transplant. No BOOP or BO was diagnosed following T-cell depletion (p<0.05). Chronic GVHD was ascertained in all BOOP patients and appeared significantly (p<0,001) more frequent in the conventional transplant group. The data confirm a strong association between T-cell activity, chronic GVHD, BO and BOOP and point out the impact of T lymphocytes in the pathomechanism of BOOP.

[Medical prevention and treatment of radiation-induced pulmonary complications]. / Prévention médicale et traitement des complications pulmonaires secondaires à la radiothérapie.

Radiation-induced lung injuries mainly include the (acute or sub-acute) radiation pneumonitis, the lung fibrosis and the bronchiolitis obliterans organizing pneumonia (BOOP). The present review aims at describing the diagnostic process, the current physiopathological knowledge, and the available (non dosimetric) preventive and curative treatments. Radiation-induced lung injury is a diagnosis of exclusion, since clinical, radiological, or biological pathognomonic evidences do not exist. Investigations should necessarily include a thoracic high resolution CT-scan and lung function tests with a diffusing capacity of the lung for carbon monoxide. No treatment ever really showed efficacy to prevent acute radiation-induced lung injury, or to treat radiation-induced lung fibrosis. The most promising drugs in order to prevent radiation-induced lung injury are amifostine, angiotensin-converting-enzyme inhibitors and pentoxifylline. Inhibitors of collagen synthesis are currently tested at a pre-clinical stage to limit the radiation-induced lung fibrosis. Regarding available treatments of radiation-induced pneumonitis, corticoids can be considered the cornerstone. However, no standardized program or guidelines concerning the initial dose and the gradual tapering have been scientifically established. Alternative treatments can be prescribed, based on clinical cases reporting on the efficacy of immunosuppressive drugs. Such data highlight the major role of the lung dosimetric protection in order to efficiently prevent radiation-induced lung injury.

Intratracheal injection of adenovirus containing the human MnSOD transgene protects athymic nude mice from irradiation-induced organizing alveolitis.

PURPOSE: A dose and volume limiting factor in radiation treatment of thoracic cancer is the development of fibrosis in normal lung. The goal of the present study was to determine whether expression prior to irradiation of a transgene for human manganese superoxide dismutase (MnSOD) or human copper/zinc superoxide dismutase (Cu/ZnSOD) protects against irradiation-induced lung damage in mice. METHODS AND MATERIALS: Athymic Nude (Nu/J) mice were intratracheally injected with 10(9) plaque-forming units (PFU) of a replication-incompetent mutant adenovirus construct containing the gene for either human MnSOD, human copper/zinc superoxide dismutase (Cu/ZnSOD) or LacZ. Four days later the mice were irradiated to the pulmonary cavity to doses of 850, 900, or 950 cGy. To demonstrate adenoviral infection, nested reverse transcriptase-polymerase chain reaction (RT-PCR) was carried out with primers specific for either human MnSOD or Cu/ZnSOD transgene on freshly explanted lung, trachea, or alveolar type II cells, and immunohistochemistry was used to measure LacZ expression. RNA was extracted on day 0, 1, 4, or 7 after 850 cGy of irradiation from lungs of mice that had previously received adenovirus or had no treatment. Slot blot analysis was performed to quantitate RNA expression for IL-1, tumor necrosis factor (TNF)-alpha, TGF-beta, MnSOD, or Cu/ZnSOD. Lung tissue was explanted and tested for biochemical activity of MnSOD or Cu/ZnSOD after adenovirus injection. Other mice were sacrificed 132 days after irradiation, lungs excised, frozen in OCT, (polyvinyl alcohol, polyethylene glycol mixture) sectioned, H&E stained, and evaluated for percent of the lung demonstrating organizing alveolitis. RESULTS: Mice injected intratracheally with adenovirus containing the gene for human MnSOD had significantly reduced chronic lung irradiation damage following 950 cGy, compared to control mice or mice injected with adenovirus containing the gene for human Cu/ZnSOD or LacZ. Immunohistochemistry for LacZ protein in adenovirus LacZ (Ad-LacZ)-injected mice demonstrated expression of LacZ in both the upper and lower airway. Nested RT-PCR showed lung expression of MnSOD and Cu/ZnSOD for at least 11 days following infection with each respective adenovirus construct. Nested RT-PCR using primers specific for human MnSOD demonstrated increased expression of the human MnSOD transgene in the trachea and alveolar type II cells 4 days after virus injection on the day of irradiation. At this time point, increased biochemical activity of MnSOD and Cu/ZnSOD respectively, was detected in lungs from these two adenovirus groups, compared to each other or to control or adenovirus LacZ mice. Slot blot analysis of RNA from lungs of mice in each group following 850 cGy irradiation demonstrated decreased expression of mRNA for interleukin-I (IL-1), TNF-alpha, and transforming growth factor-beta (TGF-beta) in the MnSOD adenovirus-injected mice, compared to irradiated control, LacZ, or Cu/ZnSOD adenovirus-injected, irradiated mice. Mice receiving adenovirus MnSOD showed decreased organizing alveolitis at 132 days in all three dose groups, compared to irradiated control or Ad-LacZ, or Ad-Cu/ZnSOD mice. CONCLUSIONS: Overexpression of MnSOD in the lungs of mice prior to irradiation prevents irradiation-induced acute and chronic damage quantitated as decreased levels of mRNA for IL-1, TNF-alpha, and TGF-beta in the days immediately following irradiation, and decrease in the percent of lung demonstrating fibrosis or organizing alveolitis at 132 days. These data provide a rational basis for development of gene therapy as a method of protection of the normal lung from acute and chronic sequelae of ionizing irradiation.

Bronchiolitis obliterans organizing pneumonia in an orthotopic liver transplant patient.

A 67-year-old woman was hospitalized for progressive dyspnea on exertion. She had undergone orthotopic liver transplantation (OLT) 15 months before admission. Posttransplant therapy consisted of tacrolimus, trimethoprim/sulfamethoxazole, and prednisone (the latter two were discontinued after 1 year). Physical examination revealed fine bibasilar crackles. High-resolution chest CT demonstrated bilateral, diffuse, interstitial infiltrates. Symptoms persisted on i.v. antibiotics and bronchoscopy was performed demonstrating patchy fibroplastic plugs within air spaces consistent with bronchiolitis obliterans organizing pneumonia (BOOP). Prednisone was initiated and the patient had an uneventful recovery. BOOP was initially described as an idiopathic disease process with clinical, radiographic, pathological, and prognostic features distinguishing it from bronchiolitis obliterans and idiopathic pulmonary fibrosis. BOOP has been recognized as a complication of lung and bone marrow transplantation, but the mechanism is unknown. We report a case of BOOP after OLT to highlight the risk in all transplant patients as well as the protective effect of posttransplant prednisone.

Corticosteroids and azathioprine do not prevent radiation-induced lung injury.

The case of a man who presented with dyspnea and a dry cough six weeks after mediastinal radiotherapy for malignant thymoma is described. The patient was on prednisone (30 mg/day) and azathioprine (100 mg/day) throughout the course of radiation. The respiratory difficulties developed as the dose of prednisone was gradually decreased to 20 mg/day postradiation. Chest x-ray showed bilateral pulmonary infiltrates. Computed tomography scan of the thorax confirmed bilateral ground glass opacities, with well-defined lateral margin on the right side corresponding to the field of radiation. However, the airspace opacities extended beyond the radiation field into the periphery of the lungs together with mild airway dilation on the left side compatible with bronchiolitis obliterans organizing pneumonia (BOOP) or cryptogenic organizing pneumonia. Bronchoalveolar lavage performed on the nonirradiated area showed an intense lymphocytosis. No cause of BOOP other than radiation was found. Treatment with high dose corticosteroids (80 mg/day) resulted in rapid clinical and radiological improvement, and resolution of chest x-ray abnormalities. Focal mediastinal radiation therapy may induce diffuse lung injury including BOOP. In addition, the concurrent use of moderate dose prednisone and azathioprine during the periradiotherapy period does not prevent the development of either BOOP or classic radiation pneumonitis.

Lung transplantation: current status and future prospects.

Lung transplantation recently marked its 35th anniversary. The period has been marked by 20 years of initially slow progress followed by 15 years of explosive growth and success. In 1997 the number of lung and heart-lung transplants exceeded 1000 in the United States and 1400 worldwide. Current 1-year survival exceeds 75% for most diagnoses. Functional results are excellent and durable with first second expired volume (FEV(1)) improving from 15% to 20% of the predicted normal preoperatively to 75% to 80% of the predicted normal postoperatively in most diagnoses. Problems facing lung transplant programs during the next century include the unavailability of graft lung donors, technical limitations of explanted graft lung preservation, and the prevention and treatment of bronchiolitis obliterans syndrome. Current status and future trends for lung transplantation are reviewed.