The Mitochondrial Calcium Uniporter of Pulmonary Type 2 Cells Determines Severity of ARDS

SUMMARYAcute lung immunity to inhaled pathogens elicits defensive pneumonitis that may convert to the Acute Respiratory Distress Syndrome (ARDS), causing high mortality. Mechanisms underlying the conversion are not understood, but are of intense interest because of the ARDS-induced mortality in the ongoing Covid-19 pandemic. Here, by optical imaging of live lungs we show that key to the lethality is the functional status of mitochondrial Ca2+ buffering across the mitochondrial Ca2+ uniporter (MCU) in the lung’s alveolar type 2 cells (AT2), which protect alveolar stability. In mice subjected to ARDS by airway exposure to lipopolysaccharide (LPS), or to Pseudomonas aeruginosa, there was marked loss of MCU expression in AT2. The ability of mice to survive ARDS depended on the extent to which the MCU expression recovered, indicating that the viability of Ca2+ buffering by AT2 mitochondria critically determines ARDS severity. Mitochondrial transfer to enhance AT2 MCU expression might protect against ARDS.

The effect of tissue elastic properties and surfactant on alveolar stability

This paper presents a novel mathematical model of alveoli, which simulates the effects of tissue elasticity and surfactant on the stability of human alveoli. The model incorporates a spherical approximation to the alveolar geometry, the hysteretic behavior of pulmonary surfactant and tissue elasticity. The model shows that the alveolus without surfactant and the elastic properties of the lung tissue are always at an unstable equilibrium, with the capability both to collapse irreversibly and to open with infinite volume when the alveolus has small opening radii. During normal tidal breathing, the alveolus can becomes stable, if surfactant is added. Including the passive effect of tissue elasticity stabilizes the alveolus, further allowing the alveoli to be stable, even for lung volumes below residual volume. The model is the first to describe the combined effects of tissue elasticity and surfactant on alveolar stability. The model may be used as an integrated part of a more comprehensive model of the respiratory system, since it can predict opening pressures of alveoli.

Surfactant proteins B and C are both necessary for alveolar stability at end expiration in premature rabbits with respiratory distress syndrome

Modified natural surfactant preparations, used for treatment of respiratory distress syndrome in premature infants, contain phospholipids and the hydrophobic surfactant protein (SP)-B and SP-C. Herein, the individual and combined effects of SP-B and SP-C were evaluated in premature rabbit fetuses treated with airway instillation of surfactant and ventilated without positive end-expiratory pressure. Artificial surfactant preparations composed of synthetic phospholipids mixed with either 2% (wt/wt) of porcine SP-B, SP-C, or a synthetic poly-Leu analog of SP-C (SP-C33) did not stabilize the alveoli at the end of expiration, as measured by low lung gas volumes of ∼5 ml/kg after 30 min of ventilation. However, treatment with phospholipids containing both SP-B and SP-C/SP-C33 approximately doubled lung gas volumes. Doubling the SP-C33 content did not affect lung gas volumes. The tidal volumes were similar in all groups receiving surfactant. This shows that SP-B and SP-C exert different physiological effects, since both proteins are needed to establish alveolar stability at end expiration in this animal model of respiratory distress syndrome, and that an optimal synthetic surfactant probably requires the presence of mimics of both SP-B and SP-C.

cDNA cloning of ovine pulmonary SP-A, SP-B, and SP-C: isolation of two different sequences for SP-B

Pulmonary surfactant promotes alveolar stability by lowering the surface tension at the air-liquid interface in the peripheral air spaces. The three surfactant proteins SP-A, SP-B, and SP-C contribute to dynamic surface properties involved during respiration. We have cloned and sequenced the complete cDNAs for ovine SP-A and SP-C and two distinct forms of ovine SP-B cDNAs. The nucleotide sequence of ovine SP-A cDNA consists of 1,901 bp and encodes a protein of 248 amino acids. Ovine SP-C cDNA contains 809 bp, predicting a protein of 190 amino acids. Ovine SP-B is encoded by two mRNA species, which differ by a 69-bp in-frame deletion in the region coding for the active airway protein. The larger SP-B cDNA comprises 1,660 bp, encoding a putative protein of 374 amino acids. With the sequences reported, a more complete analysis of surfactant regulation and the determination of their physiological function in vivo will be enabled.

An alternative view of the role(s) of surfactant and the alveolar model

Currently, the study of surfactant proteins is much in vogue, but, in the early days, the physics underlying surfactant function was treated somewhat superficially, leaving assumptions that have become culturally embedded, such as the “bubble” model of the alveolus. This review selectively reexamines these assumptions, comparing each combination of alveolar model and role of surfactant for compatibility with the major features of pulmonary mechanics and alveolar stability, morphology, and fluid balance.