Asthma is a chronic inflammatory airway disease involving complex interplay between resident and infiltrative cells, which in turn are regulated by a wide range of host mediators. Identifying useful biomarkers correlating with clinical symptoms and degree of airway obstruction remain important to effective future asthma treatments. Transforming growth factor β (TGF-β) is a major mediator involved in pro-inflammatory responses and fibrotic tissue remodeling within the asthmatic lung. Its role however, as a therapeutic target remains controversial. The aim of this review is to highlight its role in severe asthma including interactions with adaptive T-helper cells, cytokines and differentiation through regulatory T-cells. Associations between TGF-β and eosinophils will be addressed and the effects of genetic polymorphisms of the TGF-β1 gene explored in the context of asthma. We highlight TGF-β1 as a potential future therapeutic target in severe asthma including its importance in identifying emerging clinical phenotypes in asthmatic subjects who may be suitable for individualized therapy through TGF-β modulation.

Aspergillus moulds exist ubiquitously as spores that are inhaled in large numbers daily. Whilst most are removed by anatomical barriers, disease may occur in certain circumstances. Depending on the underlying state of the human immune system, clinical consequences can ensue ranging from an excessive immune response during allergic bronchopulmonary aspergillosis to the formation of an aspergilloma in the immunocompetent state. The severest infections occur in those who are immunocompromised where invasive pulmonary aspergillosis results in high mortality rates. The diagnosis of Aspergillus-associated pulmonary disease is based on clinical, radiological, and immunological testing. An understanding of the innate and inflammatory consequences of exposure to Aspergillus species is critical in accounting for disease manifestations and preventing sequelae. The major components of the innate immune system involved in recognition and removal of the fungus include phagocytosis, antimicrobial peptide production, and recognition by pattern recognition receptors. The cytokine response is also critical facilitating cell-to-cell communication and promoting the initiation, maintenance, and resolution of the host response. In the following review, we discuss the above areas with a focus on the innate and inflammatory response to airway Aspergillus exposure and how these responses may be modulated for therapeutic benefit.

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Summary A new type of experimental procedure was developed to study iron control chemicals in acidizing treatments (citric acid, nitrilotriacetic acid, and acetic acid) at temperatures from 25 to 95°C. This procedure gives plots of iron in solution versus equilibrium pH, while previous work has generally studied iron concentration in completely spent acid solutions. Hydrochloric acid concentrations of 7.5 to 28 wt %, sodium chloride concentrations of 0 and 5 wt %, and iron (III) concentrations from 1000 to 10 000 mg/kg were examined with varying concentrations of commonly used iron control chemicals. A systematic study of this kind has not previously been reported in the literature. The following new results were found:Iron (III) hydroxide precipitated from spent acid at much lower values of pH than are generally believed in the literature. The general belief is that iron (III) hydroxide precipitation begins at a pH of about 2.2 and is complete at a pH of 3.3. From experimental results, precipitation begins at pH values of about 1 and is nearly complete by pH 2 at 25°C.As the temperature was increased, iron (III) became significantly less soluble in the spent acid. This means that iron (III) hydroxide precipitation is potentially more damaging to the formation than generally believed.Time-dependent iron precipitation can occur in the absence of iron control chemicals.Time-dependent precipitation of ferric/calcium complexes with nitrilotriacetic acid (NTA) and citric acid was found. In partially spent acid, precipitation of previously unreported complexes containing an iron/calcium/chelating agent in a 1/1/1 mole ratio was observed. This behavior is important because of potential formation damage during the acidizing treatment itself, or during shut-in of the well after stimulation.Synergism with citric acid/acetic acid mixtures was found. These two iron control chemicals were able to prevent iron precipitation better in combination than individually. Introduction Iron compounds that precipitate during acidizing can reduce reservoir permeability in the critical near-wellbore area. This iron can originate from contaminated acid, dissolution of rust in the coiled tubing or well casing, from iron-containing minerals in the formation, from corrosion products present in the wellbore, or from surface equipment/tanks used during acid jobs. Iron can be present in either the +2 or the +3 oxidation state. At equilibrium, all iron will be in the +3 state in an oxidizing environment. This will occur in the presence of air in surface facilities. In a reducing environment, the +2 state is favored (normal reservoir conditions or in the presence of hydrogen sulfide). It has been observed in field samples that the ratio of iron (II) to iron (III) in spent acidizing fluids is about 5 to 1. 1,2 This ratio can vary significantly, depending on the nature of the well and the formation. Both iron (II) and iron (III) can lead to precipitate formation under certain conditions. However, most damage will occur from precipitation of iron (III) hydroxide because of its lower solubility in spent acid. Fig. 1 shows some common iron precipitation reactions. Iron (III) hydroxide precipitates as the pH increases above 1. Iron (II) hydroxide precipitates at pH values greater than about 6, making it less of a problem in acidizing. However, if hydrogen sulfide is present, then iron (II) can precipitate as iron (II) sulfide. It is also possible for iron (III) to be reduced by hydrogen sulfide, leading to precipitation of elemental sulfur. Sulfur in the formation is very difficult to remove, because it is not soluble in acids. Iron (II) can also form iron (II) carbonate as the acid is spent. Fig. 2 shows the precipitation equilibria for iron (III) hydroxide. The dotted lines are not bonds, they are used to help outline the octahedral structure of the molecule. It is important to remember that in solution, iron (III) is generally six-coordinate, and that the water and hydroxide groups are not tightly bound to the iron. They can exchange with each other or with other groups in solution. As hydroxide exchanges with the water molecules, the charge of the iron complex decreases. The neutral ferric hydroxide can easily precipitate from solution. Sources of Iron. At each stage of an acidizing treatment, there is potential for contamination of the acid with iron compounds. Before injection, acid can dissolve rust in storage or mixing tanks. 1–3 Rust dissolution leads to a mixture of iron (II) and iron (III) in solution, but dissolved oxygen in the acid will rapidly oxidize iron (II) to iron (III). During acid injection, millscale in new tubing,3 or iron-containing corrosion products in tubing 1,2,4,5 can be dissolved, resulting in large amounts of iron in solution. Corrosion products formed with oxygen in injection wells contain a mixture of Fe (II) and Fe (III). Corrosion products formed in production wells, even with trace amounts of H2S will be almost completely iron (II) compounds. Acid corrosion of steel tubing can occur to produce iron (II), and metallic iron can react with iron (III) to produce iron (II).1,2 Coulter and Gougler6 and Gougler et al.7 measured iron content in acid solutions at four different points in the acidizing process. They examined cleanup treatments of new wells only, before perforating. Acid was pumped down new tubing and up the annulus. They measured the iron content of the raw acid before transport, after transport, at the well head, and at the return line. Iron concentrations at the wellhead varied from 200 to 3500 mg/L, while returning acid showed iron concentrations of 9000 to 100 000 mg/L. Coulter and coworkers recommend pickling the tubing and annulus without the addition of iron control chemicals. The acid treatment can then be done with iron control additives sufficient to handle 1000 to 2000 mg/L of dissolved iron. Walker et al.5 showed how thin deposits of iron sulfide scale on tubing can lead to large quantities of iron (II) in solution during acid treatment. Iron sulfide reprecipitation becomes a concern when sulfide scales are present, even if hydrogen sulfide concentrations are very low. Various types of iron-containing scale can be present in production tubing, and these have been summarized by Walker et al.5

Cystic Fibrosis (CF) is a genetic disease characterised by a deficit in epithelial Cl− secretion which in the lung leads to airway dehydration and a reduced Airway Surface Liquid (ASL) height. The endogenous lipoxin LXA4 is a member of the newly identified eicosanoids playing a key role in ending the inflammatory process. Levels of LXA4 are reported to be decreased in the airways of patients with CF. We have previously shown that in normal human bronchial epithelial cells, LXA4 produced a rapid and transient increase in intracellular Ca2+. We have investigated, the effect of LXA4 on Cl− secretion and the functional consequences on ASL generation in bronchial epithelial cells obtained from CF and non-CF patient biopsies and in bronchial epithelial cell lines. We found that LXA4 stimulated a rapid intracellular Ca2+ increase in all of the different CF bronchial epithelial cells tested. In non-CF and CF bronchial epithelia, LXA4 stimulated whole-cell Cl− currents which were inhibited by NPPB (calcium-activated Cl− channel inhibitor), BAPTA-AM (chelator of intracellular Ca2+) but not by CFTRinh-172 (CFTR inhibitor). We found, using confocal imaging, that LXA4 increased the ASL height in non-CF and in CF airway bronchial epithelia. The LXA4 effect on ASL height was sensitive to bumetanide, an inhibitor of transepithelial Cl− secretion. The LXA4 stimulation of intracellular Ca2+, whole-cell Cl− currents, conductances and ASL height were inhibited by Boc-2, a specific antagonist of the ALX/FPR2 receptor. Our results provide, for the first time, evidence for a novel role of LXA4 in the stimulation of intracellular Ca2+ signalling leading to Ca2+-activated Cl− secretion and enhanced ASL height in non-CF and CF bronchial epithelia.