Immunopathogenetic and Pharmacological Aspects of Interstitial Lung Diseases

Abstract

Interstitial lung diseases (ILDs) are inflammatory diseases characterized by slow and progressive destruction of alveolar-capillary functional units, often leading to respiratory failure and death. A first stage of alveolitis and a following stage of fibrosis provoke an anatomical distortion of the peripheral airways and the interstitium, and for their smoldering evolution and non-specificity of symptoms ILDs may remain undiagnosed and untreated for a long time. In this review we exploited the immunopathogenetic aspects and the therapeutical approaches to this frequently unrecognized and severe disease. DefinitionInterstitial lung diseases (lLDs) are inflammatory diseases characterized by alveolar and lung interstitium alterations, which cause progressive scarring of lung tissue followed by a change in peripheral airways and lung blood vessels, often evolving into respiratory failure. The incidence in the general population is about 80 cases out of 100,000 inhabitants, for men, and 70 cases out of 100,000 inhabitants, for women. AnatomyThe damage to lung parenchyma is caused by activated inflammatory cells accumulated in the alveolar structures. The low respiratory tract is made up of alveoli (cluster emanations of ending bronchioles) and vascular network (arterioles, capillaries and lung venules) (Fig. la). Alveolar walls are covered by a single layer of epithelial cells (95% of type I, flat and covering, and 5% of type II, globose and producing surfactant) laying on the basal membrane continuing in the alveolar interstitium, which contains fibroblasts and connective matrix. Capillaries pass through the alveolar interstitium in eccentric position and in the point of confluence of the alveoli, where interstitium extends, there are lymphatic vessels which contribute towards the continuous drainage of liquids and solutes accumulating in the interstitium /mmunopathogenesisThe essential evolutive phases of ILD can be represented in three main aspects. The initial alterations mostly evolve in an alveolitic phase. This is probably the only partly reversible process stage, provided that the exposition to the damaging aetiological agent stops. This phase is characterized by an abundant protein-rich alveolar exudate,

Protracted Oxidative Alterations in the Mechanism of Hematopoietic Acute Radiation Syndrome

“…, ROS, RNS, and reactive products of oxidation of lipids, proteins, and nucleic acids); (ii) the subsequent proteotoxic stress and numerous deleterious targeted and non-targeted genotoxic effects; and (iii) induction of a cascade of adaptive responses in order to sustain the imbalanced proteostasis ( i.e. , homeostasis of the proteome), genomic homeostasis and the altered lipid and general metabolomic profiles [ 4 , 6 , 7 , 11 , 16 , 18 , 27 , 28 , 35 , 36 , 38 , 42 , 43 , 45 , 66 , 76 , 79 , 83 , 91 , 92 , 94 , 97 , 98 ]. In hARS the line of these events may have a protracted character and contribute to increase in susceptibility of sensitive tissues to a secondary hit caused by bacterial inflammagens appeared in circulation due to delayed bacterial breach of tissue barriers.…”

“…Evidently, these alterations are leading factors that provoke the further bacterial breach of the gut mucosal and blood immune barriers, and induce sepsis. In the mouse model of hARS the appearance of moribund animals occurs after 10–12 days following IR; while the animal loss is continuing over 7–10 days [ 10 , 17 , 20 , 21 , 23 , 77 , 91 ]. Dramatic metabolic changes occur within this post-IR period that can include oxidative, nitrative, and carbonyl stress to sensitive tissues, e.g., the bone marrow and small intestine [ 18 , 20 , 24 , 44 , 49 , 77 , 78 ].…”

“…A growing body of data suggests emerging role of “radioresistant” lineages, such as Paneth cells, mural cells, microglia, astrocytes, stromal cells, etc. , in reactive pro-inflammatory and cytotoxic effects on progenitor cell in dose limited tissues [ 49 , 57 , 77 , 91 , 92 , 94 ]. Thus, protracted pro-oxidative effects in irradiated bone marrow, vasculature, brain and intestine were attributed to activation ROS-producing mechanisms in microglia, astrocytes, and mural cells, to up-regulation of NO-producing mechanisms, and to accumulation of lipid-derived carbonyl species in gut crypt cells and stromal cells [ 43 , 49 , 57 , 77 , 91 , 92 , 94 ].…”

“…, in reactive pro-inflammatory and cytotoxic effects on progenitor cell in dose limited tissues [ 49 , 57 , 77 , 91 , 92 , 94 ]. Thus, protracted pro-oxidative effects in irradiated bone marrow, vasculature, brain and intestine were attributed to activation ROS-producing mechanisms in microglia, astrocytes, and mural cells, to up-regulation of NO-producing mechanisms, and to accumulation of lipid-derived carbonyl species in gut crypt cells and stromal cells [ 43 , 49 , 57 , 77 , 91 , 92 , 94 ]. These phenomena can cause susceptibility of major tissue barriers to post-radiation remodeling and their loss of homeostatic control [ 16 , 20 , 44 , 51 , 92 , 94 , 95 ].…”