Recruitment of inflammatory cells leads to Loss of alveolar capillary membrane integrity

Acute lung injury followed by normal repair of the alveolar capillary membrane (ACM) results in rapid resolution of the tissue injury and restoration of tissue integrity and function. The irreversible loss of ACM integrity occurs when 1) acute inflammation is not able to get rid of the toxic substance or invading pathogen (this happens following exposure to a toxic substance that is persistent or when the host is repeatedly exposed to the substance over a long period of time, 2) acute inflammation, originally incited to protect the host from external stimuli and to maintain normal homeostasis, by itself damages the host, resulting in tissue injury, and 3) the host fails to initiate a resolution response, which is essential to override the self-perpetuating inflammation response (Nathan, 2002). Loss of type-1 alveolar epithelial cells (AEC1s) and endothelial cells, the collapse of alveolar structures and fusion of basement membranes, and persistent proliferation of type II alveolar epithelial cells (AEC2s) on a damaged extracellular matrix, mark this phase (Barosova et al., 2020; Blum et al., 2014; Inoue et al., 2009; Janga et al., 2018; Marcus et al., 1997; Nemmar et al., 2016; Strieter and Mehrad, 2009). The lung tissues from patients diagnosed with idiopathic pulmonary fibrosis (IPF) show ultrastructural damage to the ACM with type-1 pneumocyte and endothelial cell injury (Strieter and Mehrad, 2009). In rodents treated with bleomycin, the damaged ACM resembles that seen in the fibrotic human lung (Grande et al., 1998).

In the context of lung fibrosis, data supporting quantitative dose-response relationships between the individual KEs is scarce. A majority of the mechanistic studies investigating the role of inflammation in lung fibrosis report acute neutrophilic inflammation and how altering neutrophil influx acutely after exposure to a toxic substance alters the end fibrotic outcome. However, these studies do not characterise the impact on immediate downstream KEs including the loss of ACM integrity or chronic inflammation in the absence of acute neutrophilia. Few studies have shown such concordance. For example, in mice exposed to different doses of bleomycin, total number of cells in BALF increased in a dose-dependent manner with predominant neutrophil phenotype at 7 days post-exposure and macrophage dominance at 24 days post-exposure (Kim et al., 2010). Other studies have shown that upon onset of chronic inflammation, secondary stimuli such as persisting toxic substance can make the injured tissue highly sensitive to acute inflammatory stimuli and may in turn fuel the ongoing chronic inflammation and affect the disease process (Ma et al., 2016).