A Real-World Multicenter Retrospective Observational Study on Polish Experience with Nintedanib Therapy in Patients with Idiopathic Pulmonary Fibrosis: The PolExNIB Study.

Nintedanib is a disease-modifying agent licensed for the treatment of IPF. Data on Polish experience with nintedanib in IPF are lacking. The present study aimed to describe the safety and efficacy profiles of nintedanib in a large real-world cohort of Polish patients with IPF. This was a multicenter, retrospective, observational study of IPF patients treated with nintedanib between March 2018 and October 2021. Data collection included baseline clinical characteristics, results of pulmonary function tests (PFTs), and a six-minute walk test (6MWT). Longitudinal data on PFTs, 6MWT, adverse drug reactions (ADRs), and treatment persistence were also retrieved. A total of 501 patients (70% male) with a median age of 70.9 years (IQR 65-75.7) were included in this study. Patients were followed on treatment for a median of 15 months (7-25.5). The majority of patients (66.7%) were treated with the full recommended dose of nintedanib and 33.3% of patients were treated with a reduced dose of a drug. Intermittent dose reductions or drug interruptions were needed in 20% of patients. Over up to 3 years of follow-up, pulmonary function remained largely stable with the minority experiencing disease progression. The most frequent ADRs included diarrhea (45.3%), decreased appetite (29.9%), abdominal discomfort (29.5%), weight loss (32.1%), nausea (20.8%), fatigue (19.2%), increased liver aminotransferases (15.4%), and vomiting (8.2%). A total of 203 patients (40.5%) discontinued nintedanib treatment due to diverse reasons including ADRs (10.2%), death (11.6%), disease progression (4.6%), patient's request (6.6%), and neoplastic disease (2.2%). This real-world study of a large cohort of Polish patients with IPF demonstrates that nintedanib therapy is safe, and is associated with acceptable tolerance and disease stabilization. These data support the findings of previously conducted clinical trials and observational studies on the safety and efficacy profiles of nintedanib in IPF.

Spontaneous pneumomediastinum as a complication of COVID-19.

In December 2019, an atypical form of severe pneumonia emerged in Wuhan in China's Hubei province, which in February 2020 was named COVID-19. The disease may have features of interstitial pneumonia and severe respiratory failure requiring intensive oxygen therapy. Spontaneous pneumomediastinum is a rare pathological condition with air in the mediastinum outside the trachea, oesophagus and bronchi. It is potentially life-threatening complication of both invasive and non-invasive mechanical ventilation. There have been reports that it may complicate the course of interstitial lung disease in the course of COVID-19. The report describes two cases of young patients who spontaneously developed this complication. Immediate diagnose is important in order to applicate adequate procedures.

Guidelines of the Polish Respiratory Society on the Diagnosis and Treatment of Progressive Fibrosing Interstitial Lung Diseases Other than Idiopathic Pulmonary Fibrosis.

The recommendations were developed as answers to previously formulated questions concerning everyday diagnostic and therapeutic challenges. They were developed based on a review of the current literature using the GRADE methodology. The experts suggest that PF-ILD be diagnosed based on a combination of different criteria, such as the aggravation of symptoms, progression of radiological lesions, and worsening of lung function test parameters. The experts recommend a precise diagnosis of an underlying disease, with serological testing for an autoimmune disease always being included. The final diagnosis should be worked out by a multidisciplinary team (MDT). Patients with an interstitial lung disease other than IPF who do not meet the criteria for the progressive fibrosis phenotype should be monitored for progression, and those with systemic autoimmune diseases should be regularly monitored for signs of interstitial lung disease. In managing patients with interstitial lung disease associated with autoimmune diseases, an opinion of an MDT should be considered. Nintedanib rather than pirfenidon should be introduced in the event of the ineffectiveness of the therapy recommended for the treatment of the underlying disease, but in some instances, it is possible to start antifibrotic treatment without earlier immunomodulatory therapy. It is also admissible to use immunomodulatory and antifibrotic drugs simultaneously. No recommendations were made for or against termination of anti-fibrotic therapy in the case of noted progression during treatment of a PF-ILD other than IPF. The experts recommend that the same principles of non-pharmacological and palliative treatment and eligibility for lung transplantation should be applied to patients with an interstitial lung disease other than IPF with progressive fibrosis as in patients with IPF.

Guidelines of the Polish Respiratory Society on the Diagnosis and Treatment of Progressive Fibrosing Interstitial Lung Diseases Other than Idiopathic Pulmonary Fibrosis

The recommendations were developed as answers to previously formulated questions concerning everyday diagnostic and therapeutic challenges. They were developed based on a review of the current literature using the GRADE methodology. The experts suggest that PF-ILD be diagnosed based on a combination of different criteria, such as the aggravation of symptoms, progression of radiological lesions, and worsening of lung function test parameters. The experts recommend a precise diagnosis of an underlying disease, with serological testing for an autoimmune disease always being included. The final diagnosis should be worked out by a multidisciplinary team (MDT). Patients with an interstitial lung disease other than IPF who do not meet the criteria for the progressive fibrosis phenotype should be monitored for progression, and those with systemic autoimmune diseases should be regularly monitored for signs of interstitial lung disease. In managing patients with interstitial lung disease associated with autoimmune diseases, an opinion of an MDT should be considered. Nintedanib rather than pirfenidon should be introduced in the event of the ineffectiveness of the therapy recommended for the treatment of the underlying disease, but in some instances, it is possible to start antifibrotic treatment without earlier immunomodulatory therapy. It is also admissible to use immunomodulatory and antifibrotic drugs simultaneously. No recommendations were made for or against termination of anti-fibrotic therapy in the case of noted progression during treatment of a PF-ILD other than IPF. The experts recommend that the same principles of non-pharmacological and palliative treatment and eligibility for lung transplantation should be applied to patients with an interstitial lung disease other than IPF with progressive fibrosis as in patients with IPF.

How much do we know about genetic predisposition of hypersensitivity pneumonitis?

INTRODUCTION AND OBJECTIVE: Hypersensitivity pneumonitis (HP) is an interstitial lung disease caused by iterative inhalation of various environmental agents. The clinical presentation is variable, acute HP commonly presents an inflammatory response, whereas the development and clinical consequences in chronic HP may be similar to IPF (idiopathic pulmonary fibrosis). The aim of the study is to present the latest discoveries regarding the genetic predisposition of HP. MATERIAL AND METHODS: The appropriate scientific literature was reviewed and analyzed. RESULTS: Studies have discovered relevant gene polymorphisms in HP, including polymorphisms in the major histocompatibility complex in the metalloproteinases genes. The length of the peripheral blood leukocyte telomere has been investigated and discovered to be important. Recently, the need to study miRNAs in ILD (interstitial lung disease) has been highlighted. CONCLUSIONS: Exposed HP developed only in some people and a genetic susceptibility significantly increases the risk. Further more current studies on large groups of patients are needed to learn more about the genetic predisposition and risk factors of HP.

Timber-colonizing gram-negative bacteria as potential causative agents of respiratory diseases in woodworkers.

OCCURRENCE: Gram-negative bacteria occur commonly in the inner tissues of stored coniferous and deciduous timber, showing a marked variation in numbers. The greatest maximal numbers are found in the sapwood of coniferous timber. The common constituents of the Gram-negative biota are potentially pathogenic species of Enterobacteriaceae family of the genera Rahnella, Pantoea, Enterobacter, and Klebsiella. The air of wood-processing facilities is polluted with the wood-borne Gram-negative bacteria and produced by them endotoxin, as demonstrated worldwide by numerous studies. EFFECTS: There are three potential pathways of the pathogenic impact of wood-borne Gram-negative bacteria on exposed woodworkers: allergic, immunotoxic, and infectious. Allergic impact has been underestimated for a long time with relation to Gram-negative bacteria. Hopefully, the recent demonstration of the first documented case of hypersensitivity pneumonitis (HP) in woodworkers caused by Pantoea agglomerans which developed in extremely large quantities in birch sapwood, would speed up finding of new wood-related cases of HP caused by Gram-negative bacteria. The second pathway is associated with endotoxin, exerting strong immunotoxic (excessively immunostimulative) action. It has been demonstrated that endotoxin is released into wood dust in the form of nano-sized microvesicles, by peeling off the outer membrane of bacteria. Endotoxin microvesicles are easily inhaled by humans together with dust because of small dimensions and aerodynamic shape. Afterwards, they cause a nonspecific activation of lung macrophages, which release numerous inflammatory mediators causing an inflammatory lung reaction, chest tightness, fever, gas exchange disorders, and bronchospasm, without radiographic changes. The resulting disease is known as "Organic Dust Toxic Syndrome" or "toxic pneumonitis." The potential third pathway of pathogenic impact is infection. The suspected species is Klebsiella pneumoniae that may occur commonly in wood dust; however, until now this pathway has not been confirmed. CONCLUSION: Summarizing, Gram-negative bacteria-inhabiting timber should be considered, besides filamentous fungi and actinobacteria, as important risk factors of occupational disease in woodworkers that could be either HP with allergenic background or toxic pneumonitis elicited by endotoxin.

COVID 19 - Possible interrelations with respiratory comorbidities caused by occupational exposure to various hazardous bioaerosols. Part II. Clinical course, diagnostics, treatment and prevention.

INTRODUCTION AND OBJECTIVE: The course of COVID-19 caused by the SARS-CoV-2 may be aggravated by bioaerosols containing other viruses, bacteria, and fungi, occurring mainly in the occupational environment. Hence, the diagnostics and treatment of COVID-19 should address such a possibility in the anamnesis, treatment and final recommendations for avoiding of adverse exposure. ABBREVIATED DESCRIPTION OF THE STATE OF KNOWLEDGE: As SARS-CoV-2 attacks primarily the respiratory system and the severe manifestation of COVID-19 is interstitial pneumonia, diagnostics should include the following clinical and laboratory examinations: chest X-ray; high resolution computed tomography (HRCT); pulmonary function tests; arterial-blood gas test; genetic tests for the presence of SARS-CoV-2, in the future with the use of highly specific and sensitive nano-based biosensors; tests for the presence of specific immunity against the antigens of microorganisms causing other infectious or allergic pulmonary diseases (in the case of anamnestic indications). Because an universally accepted treatment for COVID-19 does not exist, the hitherto prescribed antiviral and immune-modulating drugs should be used be with caution. In many cases, a better alternative could be a safe supportive therapy, such as supplementation of the diet with probiotics, prebiotics, vitamins and microelements. SUMMARY: The most important preventive measures against COVID-19 should include: vaccination; the use of filter or surgical masks; disinfection and sterilization; maintaining of well-functioning ventilation and air conditioning systems; reduction of the community air pollution which has been identified as an important factor increasing the COVID-19 severity. In the choice of preventive measures, the above should be considered for their potential efficacy against other bioaerosols as potential disease-aggravating agents.

COVID 19 - Possible interrelations with respiratory comorbidities caused by occupational exposure to various hazardous bioaerosols. Part I. Occurrence, epidemiology and presumed origin of the pandemic.

The occupational bioaerosols containing viruses, bacteria, fungi, microbial toxins and plant or animal particles, may evoke infectious, allergic or immunotoxic diseases which may co-exist as comorbidities with COVID-19 and exacerbate the course of disease. They include hypersensitivity pneumonitis (HP) caused mostly by bacteria, fungi, and particles containing animal proteins, and immunotoxic diseases such as organic dust toxic syndrome (ODTS) and byssinosis, caused mostly by bacterial and fungal toxins. The two most probable scenarios of possible interrelations between these three comorbidities (CM) and COVID-19 are: 1) 'Triggering' - when infection with SARS-CoV-2 triggers severe CM after bioaerosol exposure; 2) 'Reverse triggering' when exposure to bioaerosol exacerbates a symptomless or mild course of COVID-19, and evokes a severe disease. The occupations mostly endangered by COVID-19 as the result of exposure to SARS-CoV-2 bioaerosol, or to other bioaerosols which may exacerbate this disease, include: health care workers, social workers, breeders of fur animals, slaughterhouse workers, workers engaged in the processing and selling of seafood, and probably also agricultural workers, mainly in the developing countries. The authors present a hypothesis for the origin of the present pandemic. It assumes that a mild form of the present SARS-CoV-2 that is supposedly circulating among the Chinese population in the eastern part of the country, mutated under the influence of as yet unknown factor(s) present in the Chinese seafood markets, probably component(s) of bioaerosols, into the virulent and highly contagious form, known as the present SARS-CoV-2, under a scenario similar to that the authors have named 'Reverse triggering'.

Pantoea agglomerans chronic exposure induces epithelial-mesenchymal transition in human lung epithelial cells and mice lungs.

Pantoea agglomerans is gram-negative bacteria widely distributed in nature. It predominates in inhalable dust from grain, herbs, and flax, and was identified as the most important cause of hypersensitivity pneumonitis (HP) in eastern Poland. To better understand the molecular mechanism of HP development studies focused on the interactions between P. agglomerans and alveolar epithelial cells as well as lung tissue with particular emphasis on the epithelial-mesenchymal transition (EMT). The studies were conducted on human normal lung epithelial NL20 cells and mice strain C57BL/6J. Cells and mice underwent chronic exposure to saline extract of P. agglomerans (SE-PA). Morphological changes were evaluated under light microscopy, the concentration of fibrosis markers was examined by the ELISA method, while the expression of genes involved in EMT was evaluated by RealTime PCR. During incubation with SE-PA epithelial cells underwent conversion and assumed fibroblast phenotype characterized by a decrease in epithelial cells markers (CDH1, CLDN1, JUP) and increase in mesenchymal cells markers (FN1, VIM, CDH2). Mice lungs collected after 14 days of SE-PA treatment revealed inflammation with marked lymphocytes infiltration. The intensified inflammatory process accompanied by increased proliferation of fibrous connective tissue was noted in mice lungs after 28 days of SE-PA exposure. Histological changes correlated with an increase of fibrosis markers (hydroxyproline, collagens), downregulation of epithelial markers (Cdh1, Cldn1, Jup, Ocln) and upregulation of myofibroblasts markers (Acta2, Cdh2, Fn1, Vim). Obtained results revealed SE-PA ability to induce EMT in human lung epithelial cells and mice lung tissue, with the scale of changes proportional to the time of treatment.

Acute hypersensitivity pneumonitis in woodworkers caused by inhalation of birch dust contaminated with Pantoea agglomerans and Microbacterium barkeri.

CASE DESCRIPTION: Five workers (2 males and 3 females) employed in a furniture factory located in eastern Poland developed hypersensitivity pneumonitis (HP) after the pine wood used for furniture production was replaced by birch wood. All of them reported onset of respiratory and general symptoms (cough, shortness of breath, general malaise) after inhalation exposure to birch dust, showed crackles at auscultation, ground-glass attenuations in HRCT examination, and lymphocytosis in the BAL examination. The diagnosis of acute HP was set in 4 persons and the diagnosis of subacute HP in one. IDENTIFICATION OF SPECIFIC ALLERGEN: Samples of birch wood associated with evoking disease symptoms were subjected to microbiological analysis with the conventional and molecular methods. Two bacterial isolates were found to occur in large quantities (of the order 108 CFU/g) in examined samples: Gram-negative bacterium of the species Pantoea agglomerans and a non-filamentous Gram-positive actinobacterium of the species Microbacterium barkeri. In the test for inhibition of leukocyte migration, 4 out of 5 examined patients showed a positive reaction in the presence of P. agglomerans and 2 in the presence of M. barkeri. Only one person showed the presence of precipitins to P. agglomerans and none to M. barkeri. In the inhalation challenge, which is the most relevant allergological test in the HP diagnostics, all patients reacted positively to P. agglomerans and only one to M. barkeri. The results indicate that P. agglomerans developing in birch wood was the main agent causing HP in the workers exposed to the inhalation of dust from this wood, while the etiologic role of M. barkeri is probably secondary. CONCLUSION: The results demonstrate that apart from fungi and filamentous actinobacteria, regarded until recently as causative agents of HP in woodworkers, Gram-negative bacteria and non-filamentous actinobacteria may also elicit disease symptoms in the workers processing wood infected with large amounts of these microorganisms. The results obtained also seem to indicate that cellular-mediated reactions are more significant for causing disease symptoms compared to those that are precipitin-mediated.

Thiram - Toxic inhalational lung injury.

INTRODUCTION: Thiram, a fungicides, is widely used on seeds and as foliar agent on turf, vegetables and fruit. It is also used in the rubber industry as a vulcanization accelerator. When absorbed through the respiratory system, it is rapidly metabolised to dimethylthiocarbamate and carbon disulphide, causing noxious effects. A brief review is presented of the literature, centering on the interesting case of a 45-year-old woman admitted to the hospital suffering from acute respiratory failure. RESULTS: Computer tomography in angiographic option (angio-CT) showed an extensive, irregular area of ground glass in both upper lobes and apical segments of the lower lobes of the lungs. A significant enlargement of both atria was also described. There was no improvement after cardiac treatment and patient was transferred to the pulmonary department where she was succesfully treated with systemic glucocortycosteroids. The patient remains under the supervision of the pulmonary out-patient department.

[Hypersensitivity pneumonitis and idiopathic pulmonary fibrosis - case report]. / Alergiczne zapalenie pecherzyków plucnych i samoistne sródmiazszowe wlóknienie pluc ­ opis przypadku.

Hypersensitivity pneumonitis (HP), called extrinsic allergic alveolitis, is a syndrome characterized by diffuse inflammation of lung parenchyma and airways in response to the inhalation of antigens to witch the patient has been previously sensitized. The clinical presentation of HP have been categorized as acute, subacute and chronic. The patient with chronic HP may lack a history of acute episodes and usually reports the insidious onset of cough, dyspnoea, fatigue, and weight los. Idiopathic pulmonary fibrosis (IPF) is a type of lung disease that results in scarring (fibrosis) of the lungs for an unknown reason. Symptoms of IPF are the same as in chronic hypersensitivity pneumonitis and differentiation may be difficult. We present a case of patient with chronic HP, in whom the course of the end stage of the disease mimic acute exacerbations idiopathic pulmonary fibrosis.

The quality of life of farmers with chronic obstructive pulmonary disease (COPD).

Introduction and objective. COPD is a medical state characterized by chronically poor airflow, and typically worsens over time. Farmers have an increased risk of COPD because of being exposed to ammonia, hydrogen sulfide, inorganic dust, and organic dust. The quality of life of the ill depends on biomedical as well as psychosocial factors, the impact of which has not been a frequent subject of studies among COPD patients. The aim of the study was to indicate the factors that have negative and positive influence on the quality of life of farmers suffering from COPD. Materials and method. The study was conducted among 84 farmers treated for COPD in the Department of Pneumology, Oncology and Allergology of the Medical University in Lublin, Poland. The differences between the farmers concerned: severity of the disease, level of education and income, frequency of smoking tobacco and drinking alcohol, kinds of support they receive from their families, and the level of depression and anxiety experienced by the patients. Results. The study revealed that most patients suffered from depressive and anxiety disorders, and the level of depression higher among the patients who smoked more. Lack of family support had significant influence on exacerbation of the patient's depressive and anxiety symptoms. Patients who had recently experienced a critical situation presented with more severe COPD symptoms, lower quality of life and a higher level of depression. Higher income of the patients had positive influence on their quality of life. Farmers addicted to alcohol suffered from a higher level of anxiety.

Middle age enhances expression of innate immunity genes in a female mouse model of pulmonary fibrosis.

The lungs are highly sensitive to tissue fibrosis, with a clear age-related component. Among the possible triggers of pulmonary fibrosis are repeated inhalations of fine organic particles. How age affects this response, is still far from being fully understood. We examined the impact of middle-age on gene expression in pulmonary fibrosis, using the novel "inhalation challenge set" mouse model. Our results demonstrate that the response of female mice to exposure of Pantoea agglomerans extract primarily involves various immune-related pathways and cell-cell/cell-extracellular matrix interactions. We found that middle-age had a strong effect on the response to the P. agglomerans-induced lung fibrosis, featured by a more rapid response and increased magnitude of expression changes. Genes belonging to innate immunity pathways (such as the TLR signaling and the NK-cell mediated cytotoxicity) were particularly up-regulated in middle-aged animals, suggesting that they may be potential targets for the treatment of pulmonary fibrosis caused by inhalations of organic particles. Our analysis also highlights the relevance of the "inhalation challenge set" mouse model to lung aging and related pathology.

Pantoea agglomerans: a mysterious bacterium of evil and good. Part III. Deleterious effects: infections of humans, animals and plants.

Pantoea agglomerans, a bacterium associated with plants, is not an obligate infectious agent in humans. However, it could be a cause of opportunistic human infections, mostly by wound infection with plant material, or as a hospital-acquired infection, mostly in immunocompromised individuals. Wound infection with P. agglomerans usually follow piercing or laceration of skin with a plant thorn, wooden splinter or other plant material and subsequent inoculation of the plant-residing bacteria, mostly during performing of agricultural occupations and gardening, or children playing. Septic arthritis or synovitis appears as a common clinical outcome of exogenous infection with P. agglomerans, others include endophthalmitis, periostitis, endocarditis and osteomyelitis. Another major reason for clinical infection with P. agglomerans is exposure of hospitalized, often immunodeficient individuals to medical equipment or fluids contaminated with this bacterium. Epidemics of nosocomial septicemia with fatal cases have been described in several countries, both in adult and paediatric patients. In most cases, however, the clinical course of the hospital-acquired disease was mild and application of the proper antibiotic treatment led to full recovery. Compared to humans, there are only few reports on infectious diseases caused by Pantoea agglomerans in vertebrate animals. This species has been identified as a possible cause of equine abortion and placentitis and a haemorrhagic disease in dolphin fish (Coryphaena hippurus). P. agglomerans strains occur commonly, usually as symbionts, in insects and other arthropods. Pantoea agglomerans usually occurs in plants as an epi- or endophytic symbiont, often as mutualist. Nevertheless, this species has also also been identified as a cause of diseases in a range of cultivable plants, such as cotton, sweet onion, rice, maize, sorghum, bamboo, walnut, an ornamental plant called Chinese taro (Alocasia cucullata), and a grass called onion couch (Arrhenatherum elatius). Some plant-pathogenic strains of P. agglomerans are tumourigenic, inducing gall formation on table beet, an ornamental plant gypsophila (Gypsophila paniculata), wisteria, Douglas-fir and cranberry. Recently, a Pantoea species closely related to P. agglomerans has been identified as a cause of bacterial blight disease in the edible mushroom Pleurotus eryngii cultivated in China. The genetically governed determinants of plant pathogenicity in Pantoea agglomerans include such mechanisms as the hypersensitive response and pathogenicity (hrp) system, phytohormones, the quorum-sensing (QS) feedback system and type III secretion system (T3SS) injecting the effector proteins into the cytosol of a plant cell.

Pantoea agglomerans: a mysterious bacterium of evil and good. Part IV. Beneficial effects.

Pantoea agglomerans, a gammaproteobacterium of plant origin, possesses many beneficial traits that could be used for the prevention and/or treatment of human and animal diseases, combating plant pathogens, promotion of plant growth and bioremediation of the environment. It produces a number of antibiotics (herbicolin, pantocins, microcin, agglomerins, andrimid, phenazine, among others) which could be used for combating plant, animal and human pathogens or for food preservation. Japanese researchers have demonstrated that the low-molecular-mass lipopolysaccharide of P. agglomerans isolated by them and described as 'Immunopotentiator from Pantoea agglomerans 1 (IP-PA1)' reveals the extremely wide spectrum of healing properties, mainly due to its ability for the maintenance of homeostasis by macrophage activation. IP-PA1 was proved to be effective in the prevention and treatment of a broad range of human and animal disorders, such as tumours, hyperlipidaemia, diabetes, ulcer, various infectious diseases, atopic allergy and stress-induced immunosuppression; it also showed a strong analgesic effect. It is important that most of these effects could be achieved by the safe oral administration of IP-PA1. Taking into account that P. agglomerans occurs commonly as a symbiont of many species of insects, including mosquitoes transmitting the Plasmodium parasites causing malaria, successful attempts were made to apply the strategy of paratransgenesis, in which bacterial symbionts are genetically engineered to express and secrete anti-Plasmodium effector proteins. This strategy shows prospects for a successful eradication of malaria, a deadly disease killing annually over one million people, as well as of other vector-borne diseases of humans, animals and plants. Pantoea agglomerans has been identified as an antagonist of many plant pathogens belonging to bacteria and fungi, as a result of antibiotic production, competition mechanisms or induction of plant resistance. Its use as a biocontrol agent permits the decrease of pesticide doses, being a healthy and environmental-friendly procedure. The application of the preparations of this bacterium efficiently protects the stored pome, stone and citrus fruits against invasion of moulds. P. agglomerans strains associated with both rhizosphere and plant tissues (as endophytes) efficiently promote the growth of many plants, including rice and wheat, which are the staple food for the majority of mankind. The promotion mechanisms are diverse and include fixation of atmospheric nitrogen, production of phytohormones, as well as degradation of phytate and phosphate solubilizing which makes the soil phosphorus available for plants. Accordingly, P. agglomerans is regarded as an ideal candidate for an environmental-friendly bioinoculant replacing chemical fertilizers. It has been documented that the Pantoea strains show biodegradation activity on various chemical pollutants of soil and water, including petroleum hydrocarbons and toxic metals. P. agglomerans prevents the penetration of harmful industrial contaminants into deeper parts of soil by biofilm formation, and has an ability to produce hydrogen from waste. Thus, this bacterium appears as a valuable bioremediator which, in some cases, may be acquired as a cheap form of energy. In conclusion, in spite of the proven pathologic role of P. agglomerans in causing occupational diseases of allergic and/or immunotoxic background and accidental infections, the beneficial traits of this species, and of related species of Pantoea genus, are of great value for potential use in many areas of biotechnology. Hence, any restrictions on the use of these organisms and their products should be declined, providing safety precautions at work with the Pantoea biopreparations are maintained.

Impact of I/D polymorphism of ACE gene on risk of development and course of chronic obstructive pulmonary disease.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) affects more than 10% of the world's population over 40 years of age. The main exogenous risk factor is cigarette smoking; however, only 20% of smokers develop COPD, indicating that some other factors, e.g. genetic, may play an important role in the disease pathogenesis. Recent research indicates that ACE (angiotensin-converting enzyme) may be a susceptibility gene for asthma or COPD. The aim of our study was to determine the influence of I/D (insertion/deletion) polymorphism of the ACE gene (AluYa5, rs4646994) on the risk and course of COPD. MATERIAL AND METHODS: We investigated ACE I/D polymorphism in 206 COPD and 165 healthy Caucasian subjects. RESULTS: In the generalized linear model (GLZ) analysis of the influence of selected factors on presence of COPD we found a significant independent effect for male sex (repeatedly increases the risk of COPD, OR = 7.7, p = 0.049), as well as smoking or lower body mass index, but only in combination with older age (OR = 0.96, p = 0.003 and OR = 1.005, p = 0.04 respectively). Interestingly, analysis of factors which may influence the risk of a higher number of exacerbations demonstrated that occurrence of DD genotype, but only in men, is associated with a lower risk (OR = 0.7, p = 0.03) of this complication. CONCLUSIONS: We suggest that ACE may not be a susceptibility gene for the origin of COPD but a disease-modifying gene. Since the impact of I/D polymorphism of the ACE gene on COPD risk is moderate or negligible, other molecular changes, that will help predict the development of this disease, should still be sought.

Pantoea agglomerans: a mysterious bacterium of evil and good. Part II--Deleterious effects: Dust-borne endotoxins and allergens--focus on grain dust, other agricultural dusts and wood dust.

Pantoea agglomerans, a Gram-negative bacterium developing in a variety of plants as epiphyte or endophyte is particularly common in grain and grain dust, and has been identified by an interdisciplinary group from Lublin, eastern Poland, as a causative agent of work-related diseases associated with exposure to grain dust and other agricultural dusts. The concentration of P. agglomerans in grain as well as in the settled grain and flour dust was found to be high, ranging from 10(4)-10(8) CFU/g, while in the air polluted with grain or flour dust it ranged from 10(3)-10(5) CFU/m(3) and formed 73.2-96% of the total airborne Gram-negative bacteria. The concentration of P. agglomerans was also relatively high in the air of the facilities processing herbs and other plant materials, while it was lower in animal farms and in wood processing facilities. Pantoea agglomerans produces a biologically-potent endotoxin (cell wall lipopolysaccharide, LPS). The significant part of this endotoxin occurs in dusts in the form of virus-sized globular nanoparticles measuring 10-50 nm that could be described as the 'endotoxin super-macromolecules'. A highly significant relationship was found (R=0.804, P=0.000927) between the concentration of the viable P. agglomerans in the air of various agricultural and wood industry settings and the concentration of bacterial endotoxin in the air, as assessed by the Limulus test. Although this result may be interfered by the presence of endotoxin produced by other Gram-negative species, it unequivocally suggests the primary role of the P. agglomerans endotoxin as an adverse agent in the agricultural working environment, causing toxic pneumonitis (ODTS). Numerous experiments by the inhalation exposure of animals to various extracts of P. agglomerans strains isolated from grain dust, including endotoxin isolated with trichloroacetic acid (LPS-TCA), endotoxin nanoparticles isolated in sucrose gradient (VECN), and mixture of proteins and endotoxin obtained by extraction of bacterial mass in saline (CA-S), showed the ability of these extracts to evoke inflammatory and fibrotic changes in the lungs, to stimulate alveolar macrophages to produce superoxide anion (O2(-)), interleukin-1 (IL-1) and chemotactic factors for other macrophages and neutrophils, and to increase the pulmonary concentrations of toll-like receptors and chemokines. The most potent properties showed the CA-S which may be attributed to the allergenic properties of P. agglomerans proteins enhanced by the presence of the autologous endotoxin. The results of these experiments are in accord with the clinical studies which revealed a high reactivity of the agricultural and grain industry workers to allergenic extracts of P. agglomerans, and the presence in these populations of hypersensitivity pneumonitis and asthma cases caused by this bacterium. P. agglomerans has been also identified as a potential causative agent of allergic dermatitis in farmers and of allergic pulmonary disorders in cattle. In conclusion, similar to the cotton industry, also in the grain industry and in agriculture, Pantoea agglomerans should be regarded as one of the major causative agents of work-related diseases, caused by the adverse effects of protein allergens and endotoxin produced by this bacterium.

Pantoea agglomerans: a marvelous bacterium of evil and good.Part I. Deleterious effects: Dust-borne endotoxins and allergens - focus on cotton dust.

The ubiquitous Gram-negative bacterium Pantoea agglomerans (synonyms: Enterobacter agglomerans, Erwinia herbicola) is known both as an epiphytic microbe developing on the surface of plants and as an endophytic organism living inside the plants. The bacterium occurs also abundantly in plant and animal products, in the body of arthropods and other animals, in water, soil, dust and air, and occasionally in humans. From the human viewpoint, the role of this organism is ambiguous, both deleterious and beneficial: on one side it causes disorders in people exposed to inhalation of organic dusts and diseases of crops, and on the other side it produces substances effective in the treatment of cancer and other diseases of humans and animals, suppresses the development of various plant pathogens, promotes plant growth, and appears as a potentially efficient biofertilizer and bioremediator. P. agglomerans was identified as a predominant bacterium on cotton plant grown all over the world, usually as an epiphyte, rarely as pathogen. It is particularly numerous on cotton bract after senescence. During processing of cotton in mills, bacteria and their products are released with cotton dust into air and are inhaled by workers, causing respiratory and general disorders, usually defined as byssinosis. The most adverse substance is endotoxin, a heteropolymer macromolecule present in the outermost part of the cell wall, consisting of lipopolysaccharide (LPS) as a major constituent, phospholipids and protein. The numerous experiments carried out in last quarter of XXth century on laboratory animals and human volunteers supported a convincing evidence that the inhaled endotoxin produced by P. agglomerans causes numerous pathologic effects similar to those elicited by cotton dust, such as influx of free lung cells into airways and activation of alveolar macrophages which secrete mediators (prostaglandins, platelet-activating factor, interleukin-1, tumor necrosis factor) that cause accumulation of platelets in pulmonary capillaries initiating an acute and chronic inflammation resulting in endothelial cell damage and extravasation of cells and fluids into the lung interstitium. These changes cause bronchoconstriction, the decrement of lung function expressed as reduction of forced expiratory volume in one second (FEV1) and/or diffusion capacity, increase in the airway hyperreactivity and subjective symptoms such as fever, airway irritation and chest tightness. The conclusions from these experiments, performed mostly 2-3 decades ago, did not loose their actuality until recently as so far no other cotton dust component was identified as a more important work-related hazard than bacterial endotoxin. Though also other microbial and plant constituents are considered as potential causative agents of byssinosis, the endotoxin produced by Pantoea agglomerans and other Gram-negative bacteria present in cotton dust is still regarded as a major cause of this mysterious disease.