Phase Of Lung Injury Research Articles

Radiation-Induced Lung Injury-Current Perspectives and Management.

Radiotherapy plays an important role in the treatment of localized primary malignancies involving the chest wall or intrathoracic malignancies. Secondary effects of radiotherapy on the lung result in radiation-induced lung disease. The phases of lung injury from radiation range from acute pneumonitis to chronic pulmonary fibrosis. Radiation pneumonitis is a clinical diagnosis based on the history of radiation, imaging findings, and the presence of classic symptoms after exclusion of infection, pulmonary embolism, heart failure, drug-induced pneumonitis, and progression of the primary tumor. Computed tomography (CT) is the preferred imaging modality as it provides a better picture of parenchymal changes. Lung biopsy is rarely required for the diagnosis. Treatment is necessary only for symptomatic patients. Mild symptoms can be treated with inhaled steroids while subacute to moderate symptoms with impaired lung function require oral corticosteroids. Patients who do not tolerate or are refractory to steroids can be considered for treatment with immunosuppressive agents such as azathioprine and cyclosporine. Improvements in radiation technique, as well as early diagnosis and appropriate treatment with high-dose steroids, will lead to lower rates of pneumonitis and an overall good prognosis.

The Spectrum of CT Findings of COVID-19 Pneumonia: Acute Alveolar Insult and Organizing Pneumonia as Different Phases of Lung Injury and Repair.

PurposeTo analyze the findings and serial changes in chest CT lesions in 123 symptomatic patients with coronavirus disease 2019 (COVID-19).Materials and MethodsFrom February 19 to April 7, 2020, a total of 123 confirmed COVID-19 patients (male, 44; female, 79; mean age, 59.2 ± 18.6) were enrolled in this retrospective study. A total of 234 CT scans were reviewed for the following patterns: acute alveolar insult (AAI) patterns: ground-glass opacity (GGO), crazy-paving appearance, mixed pattern, and consolidation; organizing pneumonia (OP) patterns: perilobular patterns, band opacity, curvilinear opacity, reversed halo opacity, and small nodular consolidation; resolving patterns: pure GGO, remnant curvilinear, small nodular consolidation, and serial changes of lung abnormalities. We compared the proportions of AAI pattern, OP pattern, or resolving pattern with time progression and analyzed the association between the patterns and disease severity using Pearson chi-square and Fisher's exact test.ResultsPredominant CT patterns were AAI pattern (87%) in the early hospital period group (0–10 days, after the onset of symptoms), OP pattern (45.7%) in the later hospital period group (after 10 days), and resolving pattern in discharge and follow-up group (47.2% and 84.8%, respectively). The difference in the proportions of predominant CT patterns with time progression was statistically significant (p < 0.001, Pearson's chi-square test). No statistically significant association was observed between the patterns and disease severity (p = 0.055, Fisher's exact test). No fibrous changes in the lesions were observed on follow-up CT scans.ConclusionThe serial CT scans of COVID-19 patients showed the spectrum of COVID pneumonia CT manifestations as different phases of lung injury and repair.

Phenotypes and personalized medicine in the acute respiratory distress syndrome.

Although the acute respiratory distress syndrome (ARDS) is well defined by the development of acute hypoxemia, bilateral infiltrates and non-cardiogenic pulmonary edema, ARDS is heterogeneous in terms of clinical risk factors, physiology of lung injury, microbiology, and biology, potentially explaining why pharmacologic therapies have been mostly unsuccessful in treating ARDS. Identifying phenotypes of ARDS and integrating this information into patient selection for clinical trials may increase the chance for efficacy with new treatments. In this review, we focus on classifying ARDS by the associated clinical disorders, physiological data, and radiographic imaging. We consider biologic phenotypes, including plasma protein biomarkers, gene expression, and common causative microbiologic pathogens. We will also discuss the issue of focusing clinical trials on the patient’s phase of lung injury, including prevention, administration of therapy during early acute lung injury, and treatment of established ARDS. A more in depth understanding of the interplay of these variables in ARDS should provide more success in designing and conducting clinical trials and achieving the goal of personalized medicine.

Protective role of statins against ventilator-induced lung injury

We compliment Dr Muller and colleagues [1] for their experiment on the protective role of simvastatin against ventilator-induced lung injury (VILI). Their results are in line with those of a relevant study published recently by our research team; we also showed that pretreatment with statins (specifically atorvastatin) attenuates VILI [2]. By synthesizing the findings of the above contributions [1,2], one could make several points. First, given that Muller and colleagues administered simvastatin [1] while we chose atorvastatin [2], it seems that the observed benefit is a class-specific rather than a drug-specific effect; that is, it may apply to the whole class of statins. Second, the prevention of VILI by statins seems not to be species-specific; indeed, our colleagues employed mice [1], while we preferred rabbits [2]. Third, while the first study used female animals [1] and the second study used male animals [2], there were no differences in the produced results; thus, statins seem to be useful for the prevention of VILI in both sexes. This observation is important given the ongoing interest in the possibility that drug responses may differ by sex [3]. Fourth, by using different markers, both studies noted that administration of statins reduced VILI-associated hyperpermeability [1,2]. Indeed, the German group [1] used as a marker of lung permeability the human-serum-albumin bronchoalveolar lavage/plasma ratio, while we used both lung edema and ultrafiltration coefficient (Kf, c). Finally, Muller and colleagues implemented a 6-hour model of injurious mechanical ventilation to show that statins ameliorate pulmonary inflammation [1], whereas we focused on the very acute phase of lung injury, when mechanical phenomena rather than inflammation may best explain the injury [2]. In conclusion, we believe that the two papers [1,2] combined provide strong experimental evidence that a dose of statin as high as 20 mg/kg body weight administered before the induction of mechanical ventilation may protect against VILI and relevant clinical trials are thus fully justified.

Quantitative clinical radiobiology of early and late lung reactions

Purpose : To quantify the response of human lung to a course of fractionated radiotherapy based on a literature review of published clinical data. Materials and methods : Quantitative clinical radiobiology is concerned with the estimation of parameters that describe the clinical outcome of radiotherapy as a function of patient and treatment characteristics. Here, parameters describing the steepness of the dose–response curve, the response to a change in dose per fraction and to a change in overall treatment time for early and late lung injury are compiled based on published clinical studies. Results : Two phases of lung injury are seen, radiation pneumonitis and lung fibrosis. The first signs of early lung changes are seen almost immediately after irradiation. This reaction peaks after 5 to 6 months, and settles partially before 9–10 months. Around that time, the late changes become manifest and these are stable in most cases. There is an important distinction between lung injury and radiotherapy-related morbidity, as even severe changes in a small volume may not give rise to any clinical symptoms. Many assays have been developed for lung damage, and these highlight various clinical and biological aspects of lung damage. Here, the literature on steepness of dose–response curves and fractionation sensitivity is reviewed and quantified by the alpha/beta ratio of the linear-quadratic model for both radiation pneumonitis and lung fibrosis. For the early phase a significant time factor exists. Current best estimates for these radiobiological parameters are derived. Other external factors affecting these estimates are briefly discussed. Conclusions : Quantitative estimates of radiobiological characteristics of human lung are available for the pneumonitis phase where the fractionation sensitivity is in the same range as for most late-responding normal tissues. Short intensive schedules may also bear an added risk for pneumonitis as the dose recovered per day is around 0.5 Gy. For the later phase of lung fibrosis, the estimates are fewer and generally less precise. It is clear though, that the alpha/beta ratio is low, possibly 2–3 Gy. No time factor has been demonstrated for the late reaction. Due to the considerable physiological reserve capacity in the normal human lung, the relationship between damage and morbidity depends strongly on the lung volume affected. It therefore seems likely that for small volumes irradiated to high doses, the dose-limiting complications may not be due to restriction of lung function, but rather to haemorrhage and formation of fistulae.

Pulmonary fibroblast function in an acute lung injury model.

The role of pulmonary fibroblasts (PFBs) in early adult respiratory distress syndrome is poorly understood. To investigate PFB cellular function in acute lung injury, New Zealand rabbits (2 to 3 kg) were given either three daily doses of phorbol myristate acetate (PMA; 65 micrograms/kg, IV), a potent stimulator of oxygen radical formation, or saline (control). On day 4, the lungs were harvested, subjected to enzymatic digestion, and PFBs isolated via serial subculture. Proliferation was assessed via 6-hour pulsed [3H]thymidine incorporation and by creating 5-day growth curves. Confluent PFB cultures were assessed for collagen production and total protein production, as well as interleukin (IL)-1 alpha secretion. Qualitative comparisons using transmission electron micrography were also made. There were no differences between PFBs harvested from control versus PMA-treated animals in terms of growth rates, total protein, and IL-1 alpha production. However, there was a significant difference in collagen production, with the PMA-treated animals' PFBs producing 35% more collagen than controls. Transmission electron micrography revealed PMA fibroblasts to be smaller (two to three times), have more dark staining granules, and have hypertrophied smooth endoplasmic reticulum--all consistent with increased metabolic activity. This suggests that pulmonary fibrosis, a late development in adult respiratory distress syndrome, may be triggered during the acute phase of lung injury. The increase in collagen synthesis is not related to PFB proliferation or the secretion of IL-1 alpha.

Sequential changes in lung metabolism, permeability, and edema after ANTU.

Lung injury and pulmonary edema were induced in rats after intraperitoneal injection of 10 mg/kg alpha-naphthylthiourea (ANTU). The time course of development of lung injury was assessed by the clearance of 99mTc-diethylenetriamine pentaacetate (99mTcDTPA) from the lung into the blood, the pharmacokinetics of tritiated prostaglandin E2 [( 3H]PGE2) in the isolated perfused lung, and by increase in the weight ratio (wet-to-dry) of lung. Two hours after ANTU administration, the clearance of 99mTcDTPA was significantly faster than in untreated animals and implied an increase in permeability of the alveolar-capillary barrier. This change preceded the increase in wet-to-dry weight ratio of lung, which was not significant until 5 h after ANTU administration. The pharmacokinetics of [3H]PGE2 were significantly altered after ANTU and these changes persisted beyond the time when both lung weight ratio and 99mTcDTPA clearance had recovered to normal values. We conclude that both 99mTcDTPA clearance and PGE2 pharmacokinetics change in ANTU-induced lung injury but with different time courses. In the progressive phase of lung injury due to ANTU, the early change in clearance of 99mTcDTPA suggests that an increased permeation of the alveolar capillary barrier by this small molecule precedes pulmonary edema due to an increased colloid permeability of the barrier. Abnormal metabolism in the pulmonary microvasculature persists when the permeability defect and edema have recovered.