Methylprednisolone improves lung mechanics and reduces the inflammatory response in pulmonary but not in extrapulmonary mild acute lung injury in mice.

OBJECTIVE: Corticosteroids have been proposed to be effective in modulating the inflammatory response and pulmonary tissue remodeling in acute lung injury (ALI). We hypothesized that steroid treatment might act differently in models of pulmonary (p) or extrapulmonary (exp) ALI with similar mechanical compromise. DESIGN: Prospective, randomized, controlled experimental study. SETTING: University research laboratory. SUBJECTS: One hundred twenty-eight BALB/c mice (20-25 g). INTERVENTIONS: Mice were divided into six groups. In control animals sterile saline solution was intratracheally (0.05 mL, Cp) or intraperitoneally (0.5 mL, Cexp) injected, whereas ALI animals received Escherichia coli lipopolysaccharide intratracheally (10 microg, ALIp) or intraperitoneally (125 microg, ALIexp). Six hours after lipopolysaccharide administration, ALIp and ALIexp animals were further randomized into subgroups receiving saline (0.1 mL intravenously) or methylprednisolone (2 mg/kg intravenously, Mp and Mexp, respectively). MEASUREMENTS AND MAIN RESULTS: At 24 hrs, lung static elastance, resistive and viscoelastic pressures, lung morphometry, and collagen fiber content were similar in both ALI groups. KC, interleukin-6, and transforming growth factor (TGF)-beta levels in bronchoalveolar lavage fluid, as well as tumor necrosis factor (TNF)-alpha, migration inhibitory factor (MIF), interferon (IFN)-gamma, TGF-beta1 and TGF-beta2 messenger RNA expression in lung tissue were higher in ALIp than in ALIexp animals. Methylprednisolone attenuated mechanical and morphometric changes, cytokine levels, and TNF-alpha, MIF, IFNgamma, and TGF-beta2 messenger RNA expression only in ALIp animals, but prevented any changes in collagen fiber content in both ALI groups. CONCLUSIONS: Methylprednisolone is effective to inhibit fibrogenesis independent of the etiology of ALI, but its ability to attenuate inflammatory responses and lung mechanical changes varies according to the cause of ALI.

Bench-to-bedside review: the role of glycosaminoglycans in respiratory disease.

The extracellular matrix (ECM) plays a significant role in the mechanical behaviour of the lung parenchyma. The ECM is composed of a three-dimensional fibre mesh that is filled with various macromolecules, among which are the glycosaminoglycans (GAGs). GAGs are long, linear and highly charged heterogeneous polysaccharides that are composed of a variable number of repeating disaccharide units. There are two main types of GAGs: nonsulphated GAG (hyaluronic acid) and sulphated GAGs (heparan sulphate and heparin, chondroitin sulphate, dermatan sulphate, and keratan sulphate). With the exception of hyaluronic acid, GAGs are usually covalently attached to a protein core, forming an overall structure that is referred to as proteoglycan. In the lungs, GAGs are distributed in the interstitium, in the sub-epithelial tissue and bronchial walls, and in airway secretions. GAGs have important functions in lung ECM: they regulate hydration and water homeostasis; they maintain structure and function; they modulate the inflammatory response; and they influence tissue repair and remodelling. Given the great diversity of GAG structures and the evidence that GAGs may have a protective effect against injury in various respiratory diseases, an understanding of changes in GAG expression that occur in disease may lead to opportunities to develop innovative and selective therapies in the future.

Respiratory changes in a murine model of spontaneous systemic lupus erythematosus.

The pathophysiology of systemic lupus erythematosus (SLE) has been very well described in many organs. However, the relation between extracellular matrix changes and lung dynamic mechanical behaviour deserves elucidation. To that end, pulmonary mechanics, lung morphometry and the amount of collagen and elastic fibres in the alveolar septa were analysed in mice with SLE [NZB/W (New Zealand Black/White) F1] and non-diseased NZW mice (control). Static (E(st)) and dynamic (E(dyn)) elastances, difference between dynamic and static elastances (DeltaE), airway resistance (R(aw)) and viscoelastic/inhomogeneous pressure (DeltaP(2)) were determined by the end-inflation occlusion method. Lungs were removed and prepared for histology. E(st), E(dyn), DeltaE and DeltaP(2) were higher in SLE than in control group, while R(aw) was similar in both groups. SLE group showed alveolar collapse and increased amount of elastic and collagen fibres. In conclusion, SLE mice showed an increase in elastic and viscoelastic/inhomogeneous pressures that was accompanied by deposition of collagen and elastic fibres in the alveolar septa.