[Programmed necrosis and necroptosis - molecular mechanisms]. / Zaprogramowana martwica i nekroptoza ­ mechanizmy molekularne.

Programmed necrosis has been proven vital for organism development and homeostasis maintenance. Its regulatory effects on functional activity of the immune system, as well as on pathways regulating the death mechanisms in cells with diminished apoptotic activity, including malignant cells, have been confirmed. There is also increasing evidence indicating necrosis involvement in many human pathologies. Contrary to previous beliefs, necrosis is not only a passive, pathological, gene-independent process. However, the current knowledge regarding molecular regulation of programmed necrosis is scarce. In part this is due to the multiplicity and complexity of signaling pathways involved in programmed necrosis, as well as the absence of specific cellular markers identifying this process, but also the ambiguous and imprecise international terminology. This review presents the current state of the art on molecular mechanisms of programmed necrosis. In particular, its specific and frequent form, necroptosis, is discussed. The role of RIP1 and RIP3 kinases in this process is presented, as well as the diverse pathways induced by ligation of tumor necrosis factor α, to its receptor, TNFR1, i.e. cell survival, apoptosis or necroptosis.

Studies of hepatocyte growth factor in bronchoalveolar lavage fluid in chronic interstitial lung diseases.

INTRODUCTION:  Previous studies have suggested that hepatocyte growth factor (HGF) inhibits lung fibrosis as an antagonist of transforming growth factor ß (TGF­ß). OBJECTIVES:  We assessed HGF expression levels in the lower airways of patients with selected interstitial lung diseases. PATIENTS AND METHODS:  HGF levels were examined by an enzyme­linked immunosorbent assay in bronchoalveolar lavage (BAL) fluid supernatants from patients with pulmonary sarcoidosis (PS, n = 52), idiopathic pulmonary fibrosis (IPF, n = 23), nonspecific interstitial pneumonia (NSIP, n = 14), extrinsic allergic alveolitis (EAA, n = 6), bronchiolitis obliterans organizing pneumonia (BOOP, n = 8), chronic eosinophilic pneumonia (EP, n = 6), and in control subjects (n = 13). Intracellular HGF expression in BAL cells was evaluated by flow cytometry. RESULTS:  HGF concentrations were elevated in BAL fluid from nonsmokers with IPF (261 ±204 pg/ml, P <0.02), smokers with IPF (220 ±13 pg/ml, P <0.001), and smokers with PS (172 ±33 pg/ml, P <0.02), as compared with controls (148 ±17 pg/ml for nonsmokers; 137 ±9 pg/ml for smokers). HGF levels were positively correlated with TGF­ß concentrations in BAL fluid (r = 0.3; P = 0.02) and negatively-with vital capacity (r = -0.2; P = 0.02). BAL neutrophils, and, for the first time, BAL lymphocytes, were identified as intracellular HGF­positive cells. CONCLUSIONS:  Our results do not support evidence for strong antifibrotic HGF activity. The highest HGF concentrations were observed in BAL fluid from patients with IPF, and they were also positively correlated with TGF­ß levels. Thus, although the local protective mechanisms such as the HGF expression are upregulated in chronic interstitial lung diseases, they are not enough to prevent lung fibrosis.

[Programmed cell death: is it only apoptosis?]. / Zaprogramowana smierc komórkowa: czy tylko apoptoza?

Recent reports prove the necessity to modify the classical definitions of cell death. The canonical distinction between apoptosis (defined as programed cell death--PCD) and necrosis (gene independent) in no longer scientifically valid. Furthermore, more than one process mediated by intracellular genetic program has been documented, for example programmed necrosis. Diversity in definitions leads to confusion, particularly regarding specific terminology. Here we present the new unified criteria for the evaluation of cell death mechanisms as proposed by the Nomenclature Committee on Cell Death in recommendations from 2009 and 2012.

[Apoptosis of alveolar lymphocytes. Part 1: pathways of lymphocyte apoptosis]. / Apoptoza limfocytów pecherzykowych. Czesc 1--szlaki apoptozy limfocytów.

Apoptosis is a form of programmed cell death essential for maintaining homeostasis, including onset, progress and resolution of immune reactions. Two major apoptosis pathways: extrinsic (mediated by death receptors) and intrinsic (mitochondrial), were distinguished. Lymphocytes with cytotoxic activity may also initiate apoptosis of target cells by granzyme/perforin (pseudoreceptor) pathway. The specific apoptotic processes, i.e. activation induced cell death (AICD) and neglect induced death (NID), are types of extrinsic and intrinsic pathways, respectively. They both seem to be crucial in apoptosis of antigen-primed T cells during the contraction phase of inflammation. Alveolar lymphocytes (AL) are almost exclusively T effector cells, engaged in interstitial lung disease (ILD) pathophysiologies. The AL numbers in lower airways depends on recruitment to the lung, proliferation and local apoptosis. According to the references, it should be noted that AL usually do not proliferate in alveoli; their apoptosis rate accounts, on average, for 1% of cells in healthy subjects, and this is significantly decreased in disorders with lymphocytic alveolitis such as sarcoidosis and extrinsic allergic alveolitis (EAA). The mechanisms of AL apoptosis have not been completely explained. However, it is the NID process that is probably critical for the culling of T-cell response, as in EAA or sarcoidosis remission, with AICD as an auxiliary and/or modulating mechanism only. It should be emphasised that many ILDs are chronic disorders with no remission or improvement, and it is difficult to describe the AL response in terms of immune expansion/contraction.