Ajulemic acid exerts potent anti-fibrotic effect during the fibrogenic phase of bleomycin lung

Background: Ajulemic acid (AjA) is a synthetic analogue of tetrahydrocannabinol that can prevent and limit progression of skin fibrosis in experimental systemic sclerosis. In this study we investigated whether AjA also prevents and modulates lung fibrosis induced by bleomycin (BLM) when administered in mice during the inflammatory or the fibrogenic phase of the model. Methods: The anti-inflammatory and antifibrotic efficacy of AjA was evaluated in DBA/2 mice treated orally once a day starting either at day 0 (preventive treatment) or at day 8 (therapeutic treatment) after a single intratracheal instillation of BLM. AjA was given at a dose of 1 mg/kg or 5 mg/kg. Mice were sacrificed at day 8, 14 and 21 after BLM and lungs were processed for histology and morphometry, and examined for HO-proline content and for the expression of transforming growth factor beta 1 (TGF-β1), phosphorylated Smad2/3 (pSMAD2/3), connective tissue growth factor (CTGF), alpha-smooth muscle actin (α-SMA) and peroxisome proliferator-activated receptor-gamma (PPAR-γ). Results: In the 1st week after BLM challenge, an acute inflammation characterized by neutrophil and macrophage accumulation was the main change present in lung parenchyma. The "switch" between inflammation and fibrosis occurs between day 8 and 14 after BLM instillation and involves the bronchi and vasculature. In the subsequent week (at day 21 after BLM instillation) bronchiolocentric fibrosis with significant increase of tissue collagen develops. The fibrotic response evaluated by morphometry and quantified as HO-proline in lung tissue at day 21 after BLM treatment was significantly reduced in mice receiving either AjA in the inflammatory or in early fibrogenic phase. AjA induces marked change in the expression pattern of products implicated in fibrogenesis, such as TGF-β1, pSMAD2/3, CTGF and α-SMA. In addition, AjA increases significantly the number of PPAR-γ positive cells and its nuclear localization. Conclusions: AjA treatment, starting either at day 0 or at day 8 after BLM challenge, counteracts the progression of pulmonary fibrosis. The anti-fibrotic effectiveness of AjA is irrespective of timing of compound administration. Further clinical studies are necessary to establish whether AjA may represent a new therapeutic option for treating fibrotic lung diseases

Severe Reduction in Number and Function of Peripheral T Cells Does Not Afford Protection toward Emphysema and Bronchial Remodeling Induced in Mice by Cigarette Smoke

8openThe protein Lck (p56(Lck)) is a Src family tyrosine kinase expressed at all stages of thymocyte development and is required for maturation of T cells. The targeted disruption of Lck gene in mice results in severe block in thymocyte maturation with substantial reduction in the development of CD4(+)CD8(+) thymocytes, severe reduction of peripheral T cells, and disruption of T-cell receptor signaling with defective function of T-cell responses. To investigate the role of T lymphocyte in the development of cigarette smoke-induced pulmonary changes, Lck(-/-) mice and corresponding congenic wild-type mice were chronically exposed to cigarette smoke, and their lungs were analyzed by biochemical, immunologic, and morphometric methods. Smoking mice from both genotypes showed disseminated foci of emphysema and large areas of goblet cell metaplasia in bronchial and bronchiolar epithelium. Morphometric evaluation of lung changes and lung elastin determination confirmed that mice from both genotypes showed the same degree of emphysematous lesions. Thus, cigarette smoke exposure in the presence of severe reduction in number and function of peripheral T cells does not influence the development of pulmonary changes induced by cigarette smoke. The data obtained suggest that innate immunity is a leading actor in the early development of pulmonary changes in smoking mice and that the adaptive immune response may play a role at later stages.openDe Cunto, Giovanna; Lunghi, Benedetta; Bartalesi, Barbara; Cavarra, Eleonora; Fineschi, Silvia; Ulivieri, Cristina; Lungarella, Giuseppe; Lucattelli, MonicaDE CUNTO, Giovanna; Lunghi, Benedetta; Bartalesi, Barbara; Cavarra, Eleonora; Fineschi, Silvia; Ulivieri, Cristina; Lungarella, Giuseppe; Lucattelli, Monic

Genetic Ablation Of The Fpr1 Gene Prevents Emphysema In Mice Chronically Exposed To Cigarette Smoke

INTRODUCTION: Cigarette smoke (CS) is the main causative factor of COPD in man. Morphological features of COPD including emphysema and chronic bronchitis associated with mucus hypersecretion can be induced in mice by chronic CS exposure. The peptide fMLP (N-formyl-L-methionyl-L-leucyl-L-phenylalanine) is an active component of cigarette smoke (CS). fMLP interacts on the neutrophil and macrophage membranes with a high-affinity receptor subtype (FPR) and with a low-affinity subtype FPRL1 promoting a chemotactic response, superoxide anion production and degranulation. fMLP-receptors are found to be increased in the lavage fluids from cigarette smokers and subjects with COPD. To date, the role of FPRs in COPD remains poorly understood. We examined whether FPR contributes to lung damage induced by CS, by comparing the response of FPR knockout (Fpr1-/-) mice with that of wild-type (WT) C57 Bl/6 mice. METHODS and RESULTS: After chronic exposure to CS (3 cigarettes/day, 5 days/week for 7 months) WT mice showed significant foci of emphysema disseminated throughout the lung parenchyma with a significant increase of the mean linear intercept (+ 21 %) and a decrease of the internal surface area (– 13 %). Air-control groups and smoke exposed Fpr1-/- mice showed no areas of emphysema. Acute smoke exposure (5 cigarettes/day, for 3 days) caused in WT mice a 3,7 fold and a 1,3 fold increase in BALF neutrophils and macrophages, respectively. Fpr1 ablation in mice prevented after CS exposure the increase of neutrophils and macrophages by 73 and 42%, respectively. CONCLUSIONS: This study supports a role for FPR signalling in the development of CS-induced emphysema

Sfruttamento delle risorse minerarie e dinamica insediativa nella Toscana meridionale : l’esempio del territorio massetano (Comuni di Massa Marittima e Monterotondo Marittimo)

La porzione oggetto di questo contributo ricade entro i confini amministrativi dei comuni di Monterotondo Marittimo e Massa Marittima, nel cuore delle Colline Metallifere grossetane. Su questo territorio da lungo tempo si sono appuntati gli interessi di ricerca dell’insegnamento di Archeologia Medievale dell’Università di Siena, e si è posta attenzione allo studio delle dinamiche insediative e di controllo del ciclo produttivo attraverso i secoli, con uno specifico focus sul periodo medievale. Le indagini hanno evidenziato il ruolo chiave giocato da queste aree in differenti periodi storici in relazione alla presenza di importanti materie prime quali il diaspro per la Preistoria, le mineralizzazioni a solfuri misti, i significativi fenomeni di carattere idrotermale e l’alunite dall’epoca etrusca fino alla metà del XVIII secolo. In relazione a quest’ultimo aspetto forniamo infine un rapporto preliminare sui dati emersi dalla prima campagna di scavo effettuata sul sito ove si conservano i resti della settecentesca allumiera di Monteleo (Monterotondo Marittimo). prima campagna di scavo effettuata sul sito ove si conservano i resti della settecentesca allumiera di Monteleo (Monterotondo Marittimo).Dallai Luisa, Fineschi Stefania, Ponta Elisabetta, Travaglini Silvia. Sfruttamento delle risorse minerarie e dinamica insediativa nella Toscana meridionale : l’esempio del territorio massetano (Comuni di Massa Marittima e Monterotondo Marittimo). In: Mélanges de l'École française de Rome. Moyen-Age, tome 121, n°1. 2009. pp. 29-56

Sfruttamento delle risorse minerarie e dinamica insediativa nella Toscana meridionale : l’esempio del territorio massetano (Comuni di Massa Marittima e Monterotondo Marittimo)

La porzione oggetto di questo contributo ricade entro i confini amministrativi dei comuni di Monterotondo Marittimo e Massa Marittima, nel cuore delle Colline Metallifere grossetane. Su questo territorio da lungo tempo si sono appuntati gli interessi di ricerca dell’insegnamento di Archeologia Medievale dell’Università di Siena, e si è posta attenzione allo studio delle dinamiche insediative e di controllo del ciclo produttivo attraverso i secoli, con uno specifico focus sul periodo medievale. Le indagini hanno evidenziato il ruolo chiave giocato da queste aree in differenti periodi storici in relazione alla presenza di importanti materie prime quali il diaspro per la Preistoria, le mineralizzazioni a solfuri misti, i significativi fenomeni di carattere idrotermale e l’alunite dall’epoca etrusca fino alla metà del XVIII secolo. In relazione a quest’ultimo aspetto forniamo infine un rapporto preliminare sui dati emersi dalla prima campagna di scavo effettuata sul sito ove si conservano i resti della settecentesca allumiera di Monteleo (Monterotondo Marittimo). prima campagna di scavo effettuata sul sito ove si conservano i resti della settecentesca allumiera di Monteleo (Monterotondo Marittimo).Dallai Luisa, Fineschi Stefania, Ponta Elisabetta, Travaglini Silvia. Sfruttamento delle risorse minerarie e dinamica insediativa nella Toscana meridionale : l’esempio del territorio massetano (Comuni di Massa Marittima e Monterotondo Marittimo). In: Mélanges de l'École française de Rome. Moyen-Age, tome 121, n°1. 2009. pp. 29-56

Biogenic volatile isoprenoid emission and levels of natural selection

Biogenic volatile isoprenoid emission as a biological process has many worthwhile yet unanswered questions of fundamental scientific and ecological merit. Foremost among them is to understand and quantify the long-term feedback effects of volatile emission on climate and climate-driven macro-evolutionary changes. Moreover, we are now at a stage where our understanding of biogenic isoprenoid emission at the molecular and ecophysiological levels holds the key to the doors of next generation breakthroughs in isoprenoid-dependent applications in synthetic chemistry, human bio-therapeutics and agro-food industries. Like any other living trait/process, biogenic volatile isoprenoid emission has several levels of complex organization. We summarise biophysical, chemical and ecological functions of biogenic volatile isoprenoid emission highlighting aspects of evolution at different levels of natural selection.13 page(s

Genetic Ablation of the Fpr1 Gene Confers Protection from Smoking-Induced Lung Emphysema in Mice

Cigarette smoke (CS) is the main causative factor of chronic obstructive pulmonary disease (COPD). Current research supports the concept that airway inflammation is central to the development and progression of the disease. Studies have demonstrated that neutrophils are increased in COPD lungs and that neutrophilassociated products correlate with the development and severity of COPD. The peptide FMLP is an active component of CS. FMLP interacts on the neutrophil and macrophage membranes with a high-affinity receptor subtype (FPR1) and with a low-affinity subtype FPRL1, promoting a chemotactic response, superoxide anion production, and degranulation. Bacterial colonization of the lower respiratory tract and lung cell damage may represent further sources of formyl peptides in patients withCOPD.Weinvestigated the role of FPRinamousemodelonlunginflammationandemphysema induced by CS. Here, we report the novel observation that genetic ablation of the FPR1 gene (Fpr1) confers protection fromsmoking-induced lung emphysema in mice. Compared with wild-type mice, Fpr1 knockout mice displayed marked decreases in the lung migration of neutrophils and macrophages after CS exposure. Upon transgenic approach, the changes in cell numbers were accompanied by marked modulation of the expression of genes implicated in the inflammatory response. Administration of the FPR1 antagonist cyclosporineH to wild-type mice attenuated the acute inflammatory response evoked by CS. These findings may have clinical significance because current smokers and subjects with emphysema showed increased FPR expression in bronchoalveolar fluids and on peripheral neutrophils. Modulating the FPR1 signal should be explored as a potential new therapy

Can Population Genetic Structure Be Predicted from Life-History Traits?

Population genetic structure is a key parameter in evolutionary biology. Earlier comparative studies have shown that genetic structure depends on species ecological attributes and life‐history traits, but species phylogenetic relatedness had not been accounted for. Here we reevaluate the relationships between genetic structure and species traits in seed plants. Each species is characterized by a set of life‐history and ecological features as well as by its geographic range size, its heterozygote deficit, and its genetic structure at nuclear and organelle markers to distinguish between pollen‐ and seed‐mediated gene flow. We use both a conventional regression approach and a method that controls for phylogenetic relationships. Once phylogenetic conservatism and covariation among traits are taken into account, genetic structure is shown to be related with only a few synthetic traits, such as mating system for nuclear markers and seed dispersal mode or geographic range size for organelle markers. Along with other studies on invasiveness or rarity, our work illustrates the fact that predicting the fate of species across a broad taxonomic assemblage on the basis of simple traits is rarely possible, a testimony of the highly contingent nature of evolutionPeer reviewe