Pulmonary Surfactant
Lung

The effects of glucocorticoids on surfactant

Glucocorticoids (GCs) are essential to normal lung development. They participate in the regulation of important developmental events including morphological changes, and lung maturation leading to the surge of surfactant synthesis by type II epithelial (or alveolar) cells.
Type II epithelial cell maturation is regulated directly by glucocorticoids which bind to specific receptor sites and act by inducing the transcription and translation of genetic information.
The sub-cellular mechanism of action of glucocorticoids follows a general pattern that may apply for all steroid hormones. This pattern involves a three step process which is showed in Figure 1:

1. The steroids penetrate the target cells rapidly, probably by diffusion and bind monovalently to specific receptor proteins in the cytoplasm forming the hormone-receptor complex.
2. The hormone-receptor complex transfers to the nucleus where it ultimately attaches to a specific genetic region on the chromatin. The binding of the complex induces transcription of portions of the chromatin DNA to produce both messenger ( m ) and ribosomal ( r ) RNA.
3. Translation of the newly formed mRNA increases synthesis of specific steroid-induced proteins, which may range from enzymes involved in biosynthesis of necessary metabolites to structural elements of sub-cellular organelles.

Figure 1. Proposed subcellular action of steroids [ St ] and specific receptors [ R ] in pulmonary type II epithelial cells. From: Role of Glucocorticoids in Lung Maturation

The proteins induced by glucocorticoids within type II epithelial cells include the enzymes involved in the production of the pulmonary surfactant system. The main enzyme pathways implicated in the production of the phospholipid components of the pulmonary surface-active material are schematically depicted in Figure 2.

Figure 2. Main enzyme pathways implicated in the production of the phospholipid components of the pulmonary surface-active material. From: Role of Glucocorticoids in Lung Maturation

In particular, in a large number of species, glucocorticoids have been shown to stimulate fetal lung choline-phosphate cytidylyltransferase activity. This enzyme catalyzes the rate-limiting reaction in the formation of phosphatidylcholine, the major surface-active component of pulmonary surfactant, in whole lung and in type II alveolar cells.
Its activity is also positively regulated by epithelial – fibroblast, cell–cell communication: trials in vivo and in vitro have indicated that in response to glucocorticoids, the fetal lung fibroblast produces a protein, fibroblast-pneumonocyte factor, which in turn stimulates the cytidylyltransferase activity of converting choline phosphate into CDP choline. This leads to an increased maturation of type II epithelial cells, even if the mechanism by which fibroblast-pneumonocyte factor stimulates the cytidylyltransferase activity is unknown.

From: The cellular mechanism of glucocorticoid acceleration of fetal lung maturation

The positive action of glucocorticoids can be partly inhibited by androgens through the androgen receptor (AR) present in fibroblasts. The situation is showed below, in Figure 3.

Figure 3. Modulation of PTII cell maturation by steroids. Lung fibroblasts produce paracrine factors (PFs) contributing to PTII cell maturation. This fibroblastic contribution is stimulated by GC via GR, while androgens block the positive effect of GC on paracrine factor secretion through AR. From: Glucocorticoids metabolism in the developing lung: Adrenal-like synthesis pathway

Glucocorticoids accelerate morphologic differentiation of epithelial cells into type II cells, increase the rate of phosphatidylcholine synthesis, but also cause accumulation of messenger RNAs for surfactant proteins (SP) B and C. The effects of glucocorticoids on SP-A are more controversial: it seems that glucocorticoids have both stimulatory and inhibitory effects on SP-A gene expression in dependence on their concentration.
Several studies have shown that the time course of response to glucocorticoids (such as dexamethasone or cortisol) is biphasic, with early stimulation and later inhibition of SP-A accumulation. Maximal induction of SP-A occurred with 3-10 nM dexamethasone ( Figure 4a ) and ≈300 nM cortisol ( Figure 4b ) for 72 hr, and stimulation diminished at higher concentrations.

From: Glucocorticoids both stimulate and inhibit production of pulmonary surfactant protein A in fetal human lung

Figure 4. ( a ) Dexametasone and SP-A mRNA content; ( b) Cortisol and SP-A mRNA content.

For all these positive effects, glucocorticoids are administered to mothers at risk of premature delivery to reduce the risk of respiratory distress syndrome (RDS), as well as to those mothers suffering from diabetes.
In contrast to glucocorticoids, insulin generally inhibits SP gene expression, and this explains why infants of diabetic mothers, which are frequently hyperinsulinemic, have an increased incidence of neonatal respiratory distress syndrome. The levels of SP-A protein in the amniotic fluid of pregnancies complicated by diabetes mellitus are significantly less than in nondiabetic controls. Surprisingly, 100 nM cortisol plus inhibitory concentrations of insulin, increase SP-A mRNA levels: cortisol modulates the inhibitory effects of insulin on SP mRNA levels in a dose-dependent manner.

From: The combined effects of insulin and cortisol on surfactant protein mRNA levels

Glucocorticoid and thyroide hormone in ARDS

Glucocorticoids are not only used for prevention but also to treat patients with ARDS (acute/adult respiratory distress syndrome) a complex inflammatory lung injury associated with pulmonary microcirculation abnormalities and capillary thrombosis. Abnormal physiological responses in ARDS include an increase in right-to-left intrapulmonary shunt, an increase in total dead-space fraction, and a reduction of lung compliance. The clinical consequence of these diverse injury responses is impaired oxygenation and ventilation.
In patients with ARDS treated with corticosteroids for a few days, it is possible to see an increased oxygenation which is often accompanied by a decrease in the dead-space fraction.

From: Potential effects of corticosteroids on physiological dead-space fraction in acute respiratory distress syndrome

Fluid and solute resorption from the alveolus is critical in clearing fluid from lungs at birth and in pathologic conditions such as ARDS. Active alveolar epithelial ion transport is well established as the primary mechanism of fluid clearance from distal airspaces. In the current model of fluid balance in the distal lung, Na ions enter alveolar type II epithelial cells at the apical surface primarily through amiloride - sensitive sodium channels and are pumped out on the basolateral surface by Na,K-ATPase (sodium pump). This solute transport drives osmotic water transport and guarantees an adequate alveolar fluid clearance ( AFC ), which is decreased in pathologic conditions like ARDS. Thyroid hormone T3 stimulates Na,K-ATPase activity in many tissues, even in lungs, increasing the rate of clearance of alveolar fluid and sodium pump activity in alveolar type II epithelial cells. This stimulation occurred very rapidly (within 90 minutes) on direct instillation of T3 into the airspace in injured lungs and was specific, because the inactive form of the hormone rT3 (reverse-T3) had no effect. This rapidity is possible thanks to a significant increase in Na,K-ATPase activity probably because this protein is translocated from existing intracellular pools to the plasma membrane.

From: Triiodo-L-thyronine rapidly stimulates alveolar fluid clearance in normal and hyperoxia-injured lungs

Treatment of ARDS

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